Chemokine receptor binding compounds

ABSTRACT

The present invention relates to chemokine receptor binding compounds, pharmaceutical compositions and their use. More specifically, the present invention relates to modulators of chemokine receptor activity, preferably modulators of CCR5. These compounds demonstrate protective effects against infection of target cells by a human immunodeficiency virus (HIV).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 11/453,221 filed 14Jun. 2006, which claims the benefit of U.S. provisional application Ser.No. 60/792,359, filed Apr. 14, 2006, and U.S. provisional applicationSer. No. 60/691,269, filed Jun. 15, 2005. These applications areincorporated herein by reference.

TECHNICAL FIELD

This invention generally relates to novel compounds, pharmaceuticalcompositions and their use. More specifically, these novel compounds maybe modulators of chemokine receptor activity, preferably modulators ofchemokine receptor CCR5, and may further demonstrate protective effectsagainst infection in target cells by a human immunodeficiency virus(HIV). In another aspect, the compounds in the present invention may beuseful in the treatment and prevention of various inflammatory andautoimmune diseases.

BACKGROUND OF THE INVENTION

Approximately 40 human chemokines have been described that function atleast in part, by modulating a complex and overlapping set of biologicalactivities important for the movement of lymphoid cells andextravasation and tissue infiltration of leukocytes in response toinciting agents (See, for example: P. Ponath, Exp. Opin. Invest. Drugs,7:1-18, 1998). These chemotactic cytokines, or chemokines, constitute afamily of proteins, approximately 8-10 kDa in size, that are released bya wide variety of cells, to attract macrophages, T cells, eosinophils,basophils, and neutrophils to sites of inflammation and also play a rolein the maturation of cells of the immune system. Chemokines appear toshare a common structural motif that consists of 4 conserved cysteinesinvolved in maintaining tertiary structure. There are two majorsubfamilies of chemokines: the “CC” or β-chemokines and the “CXC” orα-chemokines, depending on whether the first two cysteines are separatedby a single amino acid, i.e., CXC or are adjacent, i.e., CC.

These chemokines bind specifically to cell-surface receptors belongingto the family of G-protein-coupled seven-transmembrane proteins whichare referred to as “chemokine receptors”, and mediate biologicalactivity through these receptors. The chemokine receptor is classifiedbased upon the chemokine that constitutes the receptor's natural ligand.Chemokine receptors of the β-chemokines are designated “CCR”; whilethose of the α-chemokines are designated “CXCR.” These chemokinereceptors include but are not limited to CCR1, CCR2, CCR2A, CCR2B, CCR3,CCR4, CCR5, CCR6, CXCR3 and CXCR4 (see for a complete review, Murphy etal. Pharmacol. Rev. 52(1), 145-176 (2000)).

Chemokines are considered to be principal mediators in the initiationand maintenance of inflammation (see Chemokines in Disease published byHumana Press (1999), Edited by C. Herbert; Murdoch et al. Blood 95,3032-3043 (2000)). More specifically, chemokines have been found to playan important role in the regulation of endothelial cell function,including proliferation, migration and differentiation duringangiogenesis and re-endothelialization after injury (Gupta et al., J.Biolog. Chem., 7:4282-4287, 1998). Both chemokine receptors CXCR4 andCCR5 have been implicated in the etiology of infection by humanimmunodeficiency virus (HIV).

In most instances, HIV initially binds via its gp120 envelope protein tothe CD4 receptor of the target cell. A conformational change appears totake place in the gp120 which results in its subsequent binding to achemokine receptor, such as CCR5 (Wyatt et al., Science, 280:1884-1888(1998)). HIV-1 isolates arising subsequently in the infection bind tothe CXCR4 chemokine receptor. The observed binding of another relatedretrovirus, feline immunodeficiency virus, to a chemokine receptorwithout needing to bind first to the CD4 receptor, suggests thatchemokine receptors may be the primordial obligate receptors forimmunodeficiency retroviruses.

Following the initial binding by HIV to CD4, virus-cell fusion results,which is mediated by members of the chemokine receptor family, withdifferent members serving as fusion cofactors for macrophage-tropic(M-tropic) and T cell line-tropic (T-tropic) isolates of HIV-1 (Carrollet al., Science, 276: 273-276 1997; Feng et al. Science 272, 872-877(1996); Bleul et al. Nature 382, 829-833 (1996); Oberlin et al. Nature382, 833-835 (1996); Cocchi et al. Science 270, 1811-1815 (1995); Dragicet al. Nature 381, 667-673 (1996); Deng et al. Nature 381, 661-666(1996); Alkhatib et al. Science 272, 1955-1958, (1996)). During thecourse of infection within a patient, it appears that a majority of HIVparticles shift from the M-tropic to the more aggressive pathogenicT-tropic viral phenotype (Miedema et al., Immune. Rev., 140:35 (1994);Blaak et al. Proc. Natl. Acad. Sci. 97, 1269-1274 (2000); Simmonds etal. J. Virol. 70, 8355-8360 (1996); Tersmette et al. J. Virol. 62,2026-2032, (1988); Connor, R. I., Ho, D. D. J. Virol. 68, 4400-4408(1994); Schuitemaker et al. J. Virol. 66, 1354-1360 (1992)). TheM-tropic viral phenotype correlates with the virus' ability to enter thecell following binding of the CCR5 receptor, while the T-tropic viralphenotype correlates with viral entry into the cell following bindingand membrane fusion with the CXCR4 receptor. Clinically, observationssuggest that patients who possess genetic mutations in the CCR5 or CXCR4appear resistant or less susceptible to HIV infection (Liu et al. Cell86, 367-377 (1996); Samson et al. Nature 382, 722-725 (1996); Michael etal. Nature Med. 3, 338-340 (1997); Michael et al. J. Virol. 72,6040-6047 (1998); Obrien et al. Lancet 349, 1219 (1997); Zhang et al.AIDS Res. Hum. Retroviruses 13, 1357-1366 (1997); Rana et al. J. Virol.71, 3219-3227 (1997); Theodorou et al. Lancet 349, 1219-1220 (1997)).

Despite the number of chemokine receptors which have been reported tomediate HIV entry into cells, CCR5 and CXCR4 appear to be the onlyphysiologically relevant coreceptors used by a wide variety of primaryclinical HIV-1 strains (Zhang et al. J. Virol. 72, 9307-9312 (1998);Zhang et al. J. Virol. 73, 3443-3448 (1999); Simmonds et al. J. Virol.72, 8453-8457 (1988)). Fusion and entry of T-tropic viruses that useCXCR4 are inhibited by the natural CXC-chemokine stromal cell-derivedfactor-1 (SDF-1). On the other hand, fusion and entry of M-tropicviruses that use CCR5 are inhibited by the natural CC-chemokines namely,Regulated on Activation Normal T-cell Expressed and Secreted (RANTES orCCL5) and Macrophage Inflammatory proteins (MIP-1 alpha and MIP-1 betaor CCL3 and CCL4, respectively). SDF-1 is known as CXCL12 or Pre B-cellstimulating factor (PBSF).

However, the binding of chemokine receptors to their natural ligandsappears to serve a more evolutionary and central role than only asmediators of HIV infection. The binding of the natural ligand,PBSF/SDF-1 to the CXCR4 chemokine receptor provides an importantsignaling mechanism. CXCR4 or SDF-1 knock-out mice exhibit cerebellar,cardiac and gastrointestinal tract abnormalities and die in utero (Zouet al., Nature, 393:591-594 (1998); Tachibana et al., Nature,393:591-594 (1998); Nagasawa et al. Nature 382, 635-638 (1996)).CXCR4-deficient mice also display hematopoietic defects (Nagasawa et al.Nature 382, 635-638 (1996)). Furthermore, the migration of CXCR4expressing leukocytes and hematopoietic progenitors to SDF-1 appears tobe important for maintaining B-cell lineage and localization of CD34⁺progenitor cells in bone marrow (Bleul et al. J. Exp. Med. 187, 753-762(1998); Viardot et al. Ann. Hematol. 77, 195-197 (1998); Auiti et al. J.Exp. Med. 185, 111-120 (1997); Peled et al. Science 283, 845-848 (1999);Qing et al. Immunity 10, 463-471 (1999); Lataillade et al. Blood 95,756-768 (1999); Ishii et al. J. Immunol. 163, 3612-3620 (1999); Maekawaet al. Internal Medicine 39, 90-100 (2000); Fedyk et al. J. LeukocyteBiol. 66, 667-673 (1999); Peled et al. Blood 95, 3289-3296 (2000)).

The signal provided by SDF-1 on binding to CXCR4 may also play animportant role in tumor cell proliferation and regulation ofangiogenesis associated with tumor growth (See “Chemokines and Cancer”published by Humana Press (1999); Edited by B. J. Rollins; Arenburg etal. J. Leukocyte Biol. 62, 554-562 (1997); Moore et al. J. Invest. Med.46, 113-120 (1998); Moore et al. Trends cardiovasc. Med. 8, 51-58(1998); Seghal et al. J. Surg. Oncol. 69, 99-104 (1998)). Knownangiogenic growth factors VEG-F and bFGF, up-regulated levels of CXCR4in endothelial cells, and SDF-1 can induce neovascularization in vivo(Salcedo et al. Am. J. Pathol. 154, 1125-1135 (1999)). Furthermore,leukemia cells that express CXCR4 migrate and adhere to lymph nodes andbone marrow stromal cells that express SDF-1 (Burger et al. Blood 94,3658-3667 (1999); Arai et al. Eur. J. Haematol. 64, 323-332 (2000);Bradstock et al. Leukemia 14, 882-888 (2000)).

The binding of SDF-1 to CXCR4 has also been implicated in thepathogenesis of atherosclerosis (Abi-Younes et al. Circ. Res. 86,131-138 (2000)), renal allograft rejection (Eitner et al.Transplantation 66, 1551-1557 (1998)), asthma and allergic airwayinflammation (Yssel et al. Clinical and Experimental Allergy 28, 104-109(1998); J. Immunol. 164, 5935-5943 (2000); Gonzalo et al. J. Immunol.165, 499-508 (2000)), Alzheimer's disease (Xia et al. J. Neurovirology5, 32-41 (1999)) and arthritis (Nanki et al. J. Immunol. 164, 5010-5014(2000)).

Platelets have also been shown to secrete the chemokine RANTES uponactivation, and that the presence of RANTES on the endothelium promotesthe arrest of monocytes on the inflamed endothelium, an important stepin atherogenesis as the conversion of macrophages into foam cells in thesubendothelium is a central process in atheroma formation (Tan, et al.,Expert Opin. Investig. Drugs, 12(11):1765-1776 (2003)). Hence, theinhibition or prevention of the binding of RANTES, directly orindirectly, to the CCR5 receptor could potentially attenuate thedevelopment of atherosclerosis. For example, Met_RANTES has also beenshown to inhibit the binding of monocytes to the activated endothelium(Tan, et al., supra).

In attempting to better understand the relationship between chemokinesand their receptors, recent experiments to block the fusion, entry andreplication of HIV via the CXCR4 chemokine receptor were carried outthrough the use of monoclonal antibodies or small molecules that appearto suggest a useful therapeutic strategy (Schols et al., J. Exp. Med.186:1383-1388 (1997); Schols et al., Antiviral Research 35:147-156(1997); Bridger et al. J. Med. Chem. 42, 3971-3981 (1999); Bridger etal. “Bicyclam Derivatives as HIV Inhibitors” in Advances in AntiviralDrug Design Volume 3, p 161-229; Published by JAI press (1999); Editedby E. De Clercq). Small molecules, such as bicyclams, appear tospecifically bind to CXCR4 and not CCR5 (Donzella et al., NatureMedicine, 4:72-77 (1998)). These experiments demonstrated interferencewith HIV entry and membrane fusion into the target cell in vitro.

Bicyclams were also shown to inhibit fusion and replication of felineimmunodeficiency virus (FIV) that uses CXCR4 for entry (Egberink et al.J. Virol. 73, 6346-6352 (1999)). CCR5 blocking agents include monoclonalantibodies, some which selectively block HIV coreceptor activity but notchemokine binding, and chemokine derivatives, such as truncated versionsof RANTES, Met-RANTES, and AOP-RANTES and the viral chemokine KSHVvMIP-II, all which block both chemokine and HIV interaction with CCR5but are not selective (reviewed by Murphy et al. Pharmacol. Rev. 52(1),145-176 (2000)).

Additional experiments have shown that the bicyclam dose-dependentlyinhibits binding of 125I-labeled SDF-1 to CXCR4 and the signaltransduction (indicated by an increase in intracellular calcium) inresponse to SDF-1. Thus, the bicyclam also functioned as an antagonistto the signal transduction resulting from the binding of stromal derivedfactor or SDF-1α, the natural chemokine to CXCR4. Bicyclams alsoinhibited HIV gp120 (envelope)-induced apoptosis in non-HIV infectedcells (Blanco et al. Antimicrobial Agents and Chemother. 44, 51-56(2000)).

Passive immunization with anti-MIP-1 alpha has been shown to delay theonset and reduce the severity of collagen-induced-arthritis (CIA) inmice, where the CIA model is an established murine model representinghuman rheumatoid arthritis (Szekanecz, Z., et al., AP, Seminars inImmunology, 15 (2003), p. 15-21). Other studies have also shown thatagents that block the CCR5 receptor may provide a rational approach tothe treatment of multiple sclerosis. Administration of anti-MIP-1 alphaantiserum has been shown to prevent CNS infiltration by PBMC in micewith experimental allergic encephalomyelitis, a rodent model of multiplesclerosis (Balashov, K. E., et al., Proc. Natl. Acad. Sci. USA, Vol. 96(1999), p. 6873-6878).

Other studies involving chronic rejection of transplanted hearts orcardiac allograft vasculopathy (CAV) and acute renal allograft rejectionhave shown that blocking chemokine receptors such as CCR5 may provideunique therapeutic approaches in the treatment or prevention of suchdiseases (Yun J J, et al., Circulation, 2004, Vol. 109(7), p. 932-7,Panzer U., et al., Transplantation, 2004, Vol. 78(9), p. 1341-50). Forexample, antagonism of the chemokine receptors CCR1 and CCR5 withMet-RANTES attenuated CAV development by reducing mononuclear cellrecruitment to the transplanted heart. Met-CCL5, an antagonist of CCR1and CCR5, had been tested and shown to inhibit the growth of breasttumors (Robinson S C. et al, Cancer Res., 2003, Vol. 63(23), p. 8360-5).

Chemokines, as indicated above, play an important role and areimplicated in a wide variety of human disease such as in autoimmunedisease, allograft rejection, infection, allergies, neoplasia, andvascular abnormalities. In addition to its contributory role in HIVinfection, the chemokine receptor CCR5 has been associated with diseasessuch as the inflammatory demyelinating diseases of the central nervoussystem, including multiple sclerosis and experimental autoimmuneencephalomyelitis, rheumatoid arthritis, intestinal inflammation,allograft rejection, asthma, and cardiovascular disease (reviewed inGerard et al. Natl. Immunol. 2(2), 108-115 (2001) and Luster, A., N.Eng. J. Med., 338 (7), 436-445 (1998)). The CCR5 receptor is expressedon T-lymphocytes, and macrophages and reports of CCR5 on neurons,astrocytes, capillary endothelial cells, epithelium, vascular smoothmuscle, and fibroblast have been published. The natural ligands thatbind to the CCR5 receptor, in addition to RANTES and MIP-1 alpha/beta,are monocyte chemoattractant protein 2 (MCP-2 or CCL8).

U.S. Pat. Nos. 5,583,131; 5,698,546; 5,817,807; 5,021,409; and 6,001,826which are incorporated herein in their entirety by reference, disclosecyclic compounds that are active against HIV-1 and HIV-2 in in vitrotests. It was subsequently discovered and further disclosed in PCT WO02/34745 that these compounds exhibit anti-HIV activity by binding tothe chemokine receptor CXCR4 and/or CCR5 expressed on the surface ofcertain cells of the immune system. This competitive binding therebyprotects these target cells from infection by HIV which utilize theCXCR4 receptor for entry. In addition, these compounds antagonize thebinding, signaling and chemotactic effects of the natural ligand forCXCR4, the chemokine stromal cell-derived factor 1α (SDF-1).Furthermore, these compounds demonstrate protective effects against HIVinfection of target cells by binding in vitro to the CCR5 receptor.

Additionally, U.S. Pat. No. 6,365,583 discloses that these cyclicpolyamine antiviral agents described in the above-mentionedpatents/patent applications have the effect of enhancing production ofwhite blood cells as well as exhibiting antiviral properties. Thus,these agents are useful for controlling the side-effects ofchemotherapy, enhancing the success of bone marrow transplantation,enhancing wound healing and burn treatment, as well as combatingbacterial infections in leukemia.

PCT WO 00/56729, PCT WO 02/22600, PCT WO 02/22599, and PCT WO 02/34745describe a series of heterocyclic compounds that exhibit anti-HIVactivity by binding to the chemokine receptors CXCR4 and CCR5 expressedon the surface of certain cells of the immune system. This competitivebinding thereby protects these target cells from infection by HIV whichutilize the CXCR4 or CCR5 receptors for entry. In addition, thesecompounds antagonize the binding, signaling and chemotactic effects ofthe natural ligand for CXCR4, the chemokine stromal cell-derived factor1α (SDF-1) and/or the natural ligand for CCR5, the chemokine RANTES.

The chemokine receptor, CXCR4 has been found to be associated with thevascularization of the gastrointestinal tract (Tachibana et al., Nature,393:591-594 (1998)) as well as in hematopoiesis and cerebellardevelopment (Zou et al., Nature, 393:591-594 (1998)). Interference withany of these important functions served by the binding of pre-B-cellgrowth-stimulating factor/stromal derived factor (PBSF/SDF-1) to theCXCR4 chemokine receptor results in lethal deficiencies in vasculardevelopment, hematopoiesis and cardiogenesis. Similarly, fetalcerebellar development appears to rely upon the effective functioning ofCXCR4 in neuronal cell migration and patterning in the central nervoussystem. This G-protein-coupled chemokine receptor appears to play animportant role in ensuring the necessary patterns of migration ofgranule cells in the cerebellar anlage.

Herein, we disclose compounds that have unique chemical attributes andthat exhibit protective effects against HIV infection of target cells bybinding to chemokine receptor CCR5. In addition, these compoundsantagonize the binding, signaling and chemotactic effects of the naturalligand for CCR5, the chemokine RANTES.

Citation of the above documents is not intended as an admission that anyof the foregoing is pertinent prior art. All statements as to the dateor representation as to the contents of these documents is based on theinformation available to the applicants and does not constitute anyadmission as to the correctness of the dates or contents of thesedocuments. Further, all documents referred to throughout thisapplication are hereby incorporated in their entirety by referenceherein.

DISCLOSURE OF THE INVENTION

The present invention provides novel compounds that may modulatechemokine receptors and interfere with the binding of the natural ligandthereto. More particularly, the present invention relates to novelpiperidine derivatives that may bind to chemokine receptors, preferablyCCR5 receptors.

The compounds of the present invention may be useful as agentsdemonstrating protective effects on target cells from HIV infection. Thecompounds of the present invention may also be useful for the treatmentand prevention of inflammatory and autoimmune diseases. Embodiments ofthe present invention are compounds that may act as antagonists oragonists of chemokine receptors, which may be useful as agents capableof reconstituting the immune system by increasing the level of CD4⁺cells; as antagonist agents of apoptosis in immune cells, such as CD8⁺cells, and neuronal cells; as antagonist agents of migration of humanbone marrow B lineage cells to stromal-derived factor 1, as well asother biological activities related to the ability of these compounds toinhibit the binding of chemokines to their receptors.

In one aspect, the invention provides a compound having formula (1)

and pharmaceutically acceptable salts thereof,

wherein A is carbon or sulfur;

X is oxygen, sulfur, NR², NOR², NCN, NSO₂R², NAc, NNO₂, CRNO₂, NCOR²,C(CN)₂ or CRCN, provided X is oxygen if A is sulfur;

Y is a bond, O(CR₂)_(p), S(CR₂)_(p), NR(CR₂)_(p) or (CR₂)_(p) whereinone carbon in (CR₂)_(p) may optionally be substituted and/or replacedwith N, O or S; or Y together with (CR₂)_(m) may form a 5-6 memberedring;

n and p are independently 0 to 6;

m is 1 to 2, provided m is 1 if A is carbon;

E is H or methyl;

R¹ is an optionally substituted aryl or heteroaryl;

R² is H, an optionally substituted alkyl, a carbocyclic ring, aheterocyclic ring, an aryl, or a heteroaryl; and

R³ is H; an optionally substituted alkyl, alkenyl or alkynyl; hydroxy,alkoxy, cyano, amino, amido, carboxyl, CO₂R², S═(O)_(p)R², CR═N—OR,O(CR₂)CN, NR—COR², SR²; a carbocyclic ring, a heterocyclic ring, anaryl, or a heteroaryl;

R and R⁴ are independently H, C₁₋₆ alkyl, or C₃₋₆ cycloalkyl;

wherein in each said optionally substituted alkyl, alkenyl or alkynyl, acarbon may be optionally substituted with halo, N, O, or S, and/orreplaced with N, O or S; and

each carbocyclic ring, heterocyclic ring, aryl or heteroaryl may beoptionally substituted and/or fused with a carbocyclic, aryl,heterocyclic, or heteroaryl ring.

In one embodiment of the above formula (1), R¹ is phenyl, pyrimidinyl,pyridinyl, pyridine N-oxide, thienyl, isoxazolyl or pyrazolyl, each ofwhich is optionally substituted by one or more halo, cyano, alkyl,alkoxy, amine, amide, cycloalkyl, heterocyclyl, aryl, heteroaryl, orN-oxide.

In another embodiment of the above formula (1), R² is H, an optionallysubstituted alkyl, cycloalkyl, aryl or heteroaryl, each of which isoptionally linked to one or more C₁₋₆ alkyl, alkoxy, trifluoromethyl,carboxylalkyl, cyano, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl,or N-oxide. In some examples, R² is phenyl, pyridiminyl, pyridinyl,thiazolyl, furanyl, thienyl, or imidazolyl.

In yet another embodiment of the above formula (1), R³ is H, OH, cyano,NR₂, SR, SOR, SO₂R, CO₂R, CONR₂, or an optionally substituted alkyl oralkoxy, wherein R is independently H or C₁₋₆ alkyl; or R³ may be acarbocyclic ring, a heterocyclic ring, an aryl, or a heteroaryl, each ofwhich may be optionally substituted with halo, cyano, alkyl, alkoxy,cycloalkyl, heterocyclyl, aryl, heteroaryl, or N-oxide and/or fused witha carbocyclic, aryl, heterocyclic, or heteroaryl ring. In some examples,R³ is cyclohexyl, tetrahydropyran, morpholine, phenyl optionally fusedwith a 5-6 membered heterocyclic ring, pyridinyl, thienyl, C₁₋₆ straightor branched alkyl, bicyclo[4.2.0]octa-1,3,5-triene, indolyl,benzodioxolyl, dihydrobenzofuranyl, dihydroisobenzofuranyl,benzofuranyl, dihydrobenzodioxinyl, pyrrolidin-2-one, tetrazole,imidazole, dioxolane, or isoxazole.

In another embodiment of the above formula (1), each R⁴ is hydrogen. Inother examples, n is 1. In some examples, A and Y are not bothheteroatoms.

In another aspect, the present invention provides a compound havingformula (2) or a pharmaceutically acceptable salt thereof:

and pharmaceutically acceptable salts thereof;

wherein W is oxygen, sulfur, NR², NOR², NCN, NSO₂R², NAc, NNO₂, CRNO₂,NCOR², C(CN)₂ or CRCN;

V is O, S, N-L-R³, or CR-L-R³;

L is a bond or a (CR₂)_(m) linker optionally having one carbon of(CR₂)_(m) replaced by a group selected from O, S, and NR, and m is 1-3;

R¹ is an optionally substituted aryl or heteroaryl;

R² is H, an optionally substituted alkyl, a carbocyclic ring, aheterocyclic ring, an aryl, or a heteroaryl;

R³ is H; an optionally substituted alkyl, alkenyl or alkynyl; hydroxy,alkoxy, cyano, amino, amido, COR², CO₂R², S═(O)_(p)R², CR═N—OR,O(CR₂)CN, NR—COR², SR²; a carbocyclic ring, a heterocyclic ring, anaryl, or a heteroaryl; and

R is H, C₁₋₆ alkyl, or C₃₋₆ cycloalkyl;

wherein in each said optionally substituted alkyl, alkenyl or alkynyl, acarbon may be optionally substituted with halo, N, O, or S, and/orreplaced with N, O or S; and each carbocyclic ring, heterocyclic ring,aryl or heteroaryl may be optionally substituted and/or fused with acarbocyclic, aryl, heterocyclic, or heteroaryl ring.

In one embodiment of the above formula (2), R¹ is phenyl, pyrimidinyl orpyridinyl, each optionally substituted with halo, cyano, alkyl, alkoxy,cycloalkyl, heterocyclyl, aryl, heteroaryl, or N-oxide.

In another embodiment of the above formula (2), R² is phenyl, thienyl,or imidazolyl each optionally substituted with halo, cyano, alkoxy,heterocyclyl, aryl, heteroaryl, or N-oxide; or alkyl or cycloalkyl, eachof which may be optionally substituted with halo, cyano, OR, SR, orN(R)_(m), or in which one carbon may be optionally replaced with N, O,or S.

In yet another embodiment of the above formula (2), R³ is H, C₁₋₁₀straight or branched alkyl; or R³ is a C₃₋₇ cycloalkyl, a 5-6 memberedaryl, heteroaryl or heterocyclic ring, each optionally substituted withhalo, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl,or fused with a carbocyclic or heterocyclic ring. In some examples, R³is H, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydropyran, morpholine,phenyl optionally fused to a 5-6 membered heterocyclic ring, pyridinyl,imidazole, furan, pyrimidine, thienyl, C₁₋₆ straight or branched alkyl,or bicyclo[4.2.0]octa-1,3,5-triene.

In some embodiments of the above formula (1) or (2), each R isindependently selected, and each can be H or alkyl. In some embodimentseach R is H. In other embodiments one or more occurrences of R is analkyl group, typically a C₁-C₆ alkyl group, or a cycloalkyl group,typically a C₃-C₆ cycloalkyl group. In other embodiments at least one Ris a C₁-C₆ alkyl or cycloalkyl group. Where two R groups appear on asingle atom such as in a (CR₂) unit, they may optionally be linked toform a 3-8 membered ring. Where two R groups occur on adjacent atomsthey may also be linked to form a 3-8 membered ring. In someembodiments, each optional substituent include but are not limited tohalogen, alkyl, amine, cyano, amide or heteroaryl.

The present invention also provides pharmaceutical compositionscomprising compounds having formula (1) or (2), and a pharmaceuticallyacceptable carrier. Furthermore, the present invention provides methodsfor treating a CCR5 mediated disease in a cell, tissue or organ,comprising contacting a compound having formula (1) or (2) with thesystem, thereby treating a CCR5-mediated disease. The present inventionalso provides methods for treating a CCR5 mediated-disease in a human oranimal subject, comprising administering a compound having formula (1)or (2) with the subject, thereby treating a CCR5-mediated disease.

Examples of CCR5-mediated diseases that may be treated using thecompounds of the present invention include but are not limited to HIV,an inflammatory demyelinating disease of the central nervous system, anautoimmune disease, multiple sclerosis, experimental autoimmuneencephalomyelitis, psoriatic or rheumatoid arthritis, intestinalinflammation, allograft rejection, asthma, cardiovascular disease,atherosclerosis, allergic disease, allergic rhinitis, dermatitis,conjunctivitis, hypersensitivity lung disease, hypersensitivitypneumonitis, eosinophilic pneumonia, delayed-type hypersensitivity,interstitial lung disease (ILD), idiopathic pulmonary fibrosis, ILDassociated with rheumatoid arthritis, systemic lupus erythematosus,ankylosing spondylitis, systemic sclerosis, Sjogren's syndrome,polymyositis, dermatomyositis, systemic anaphylaxis, myasthenia gravis,juvenile onset diabetes, glomerulonephritis, autoimmune thyroiditis,graft rejection, allograft rejection, graft-versus-host disease,inflammatory bowel disease, Crohn's disease, ulcerative colitis,spondyloarthropathy, scleroderma; psoriasis, inflammatory dermatosis,dermatitis, eczema, atopic dermatitis, allergic contact dermatitis,urticaria, vasculitis, eosinophilic myotis, eosinophilic fascitis, tumoror cancer.

The compounds of formula (1) or (2) may form hydrates or solvates, andmay be in any stereoisomeric forms and mixtures of stereoisomeric formsthereof. Racemate compounds may be separated into individual isomersusing known separation and purification methods. Individual opticalisomers and a mixture thereof, are included in the scope of the presentinvention.

MODES OF CARRYING OUT THE INVENTION

In one aspect, the invention provides compounds having formula (1) or(2) described above, which may be chemokine modulators of chemokinereceptors.

In more detail, the compounds may bind chemokine receptors and interferewith the binding of the natural ligand thereto, and may demonstrateprotective effects on target cells from HIV infection. The compounds maybe useful as antagonists or agonists of chemokine receptors, and arethus capable of reconstituting the immune system by increasing the levelof CD4⁺ cells; as antagonist agents of apoptosis in immune cells, suchas CD8⁺ cells, and neuronal cells; as antagonist agents of migration ofhuman bone marrow B lineage cells to stromal-derived factor 1, as wellas other biological activities related to the ability of these compoundsto inhibit the binding of chemokines to their receptors.

Chemokine antagonists that interfere in the binding of a chemokine toits receptor are useful to reconstitute the immune system by increasingthe level of CD4⁺ cells (Biard-Piechaczyk, et al., Immunol. Lett.,70:1-3 (1999)); as antagonist agents of apoptosis in immune cells, suchas CD8⁺ cells (Herbin, et al., Nature 395: 189-193, (1998)), and asantagonist agents of apoptosis in neuronal cells (Ohagen et al., J. ofVirol., 73: 897-906, (1999); and Hesselgesser, et al., Curr. Biol. 8:595-598, (1998)). Chemokine receptor antagonist agents also inhibit themigration of human bone marrow B lineage cells to stromal-derived factor1 (See e.g., E. Fedyk, et al., J of Leukocyte Biol., 66:667-783,(1999)).

The invention includes pharmaceutical compositions comprising atherapeutically effective amount of a compound of formula (1) or (2)along with at least one excipient, and methods of treating diseases ofthe human body or the bodies of other mammals with such compositions. Asused herein, the term “therapeutically effective amount” refers to theamount of a compound of formula (1) or (2) that will elicit thebiological or medical response of a cell, tissue, organ, system, animalor human that is being sought by the researcher, veterinarian, medicaldoctor, or other clinician.

The invention provides a method for blocking or interfering with thebinding by a chemokine receptor with its natural ligand, comprisingcontacting of the chemokine receptor with an effective amount of thecompound according to formula (1) or (2). The present invention alsoprovides methods of protecting target cells possessing chemokinereceptors, which binding to a pathogenic agent results in disease orpathology, comprising administering to a mammalian subject apharmaceutical composition comprising a therapeutically effective amountof the compound according to formula (1) or (2).

Furthermore, the invention provides the use of a compound of formula (1)or (2) in the manufacture of a medicament for the treatment of a diseasein which blocking or interfering with binding of a chemokine receptorwith its natural ligand is advantageous. The compound is formulated intoa composition in an amount corresponding to a therapeutically effectiveamount of a compound of formula (1) or (2).

The Invention Compounds

The invention compounds are described generally by formula (1) orformula (2).

In one aspect, the invention provides compounds having formula (1):

and pharmaceutically acceptable salts thereof,

wherein A is carbon or sulfur;

X is oxygen, sulfur, NR², NOR², NCN, NSO₂R², NAc, NNO₂, CRNO₂, NCOR²,C(CN)₂ or CRCN, provided X is oxygen if A is sulfur;

Y is a bond, O(CR₂)_(p), S(CR₂)_(p), NR(CR₂)_(p) or (CR₂)_(p) whereinone carbon in (CR₂)_(p) may optionally be substituted and/or replacedwith N, O or S; or Y together with (CR₂)_(m) may form a 5-6 memberedring;

n and p are independently 0 to 6;

m is 1 to 2, provided m is 1 if A is carbon;

E is H or methyl;

R¹ is an optionally substituted aryl or heteroaryl;

R² is H, an optionally substituted alkyl, a carbocyclic ring, aheterocyclic ring, an aryl, or a heteroaryl; and

R³ is H; an optionally substituted alkyl, alkenyl or alkynyl; hydroxy,alkoxy, cyano, amino, amido, carboxyl, CO₂R², S═(O)_(p)R², CR═N—OR,O(CR₂)CN, NR—COR², SR²; a carbocyclic ring, a heterocyclic ring, anaryl, or a heteroaryl;

R and R⁴ are independently H, C₁₋₆ alkyl, or C₃₋₆ cycloalkyl;

wherein in each said optionally substituted alkyl, alkenyl or alkynyl, acarbon may be optionally substituted with halo, N, O, or S, and/orreplaced with N, O or S; and

each carbocyclic ring, heterocyclic ring, aryl or heteroaryl may beoptionally substituted and/or fused with a carbocyclic, aryl,heterocyclic, or heteroaryl ring.

In formula (1), each occurrence of R is independently determined, andeach may be H, C1-C6 alkyl, C3-C6 cycloalkyl, or C4-C10 cycloalkylalkyl;furthermore, one or more CR₂ members in a group described as (CR₂)_(m)or (CR₂)_(n), may be replaced with a group selected from O, S, SO, SO₂,NCOR, and NR. For example, (CR₂)_(n) where n is 3 can be CH₂OCH₂, forexample.

In the above formula (1), R may be hydrogen, C₁₋₆ alkyl, C₃-C₈cycloalkyl, or C₄-C₁₀ cycloalkylalkyl. In some examples, R and R⁴ areindependently H, C₁₋₆ alkyl, or C₃-C₈ cycloalkyl. In particularexamples, R and R⁴ are each H.

In the above formula (1), R¹ may be phenyl, pyrimidinyl, pyridinyl,pyridine N-oxide, thienyl, isoxazolyl or pyrazolyl, each of which isoptionally substituted by one or more halo, cyano, alkyl, alkoxy, amine,amide, cycloalkyl, heterocyclyl, aryl, heteroaryl, or N-oxide.

In other embodiments, R¹ in formula (1) may be an optionally substitutedcyclic or acyclic alkyl or 5- or 6-membered non-aromatic heterocyclicring, each of which is optionally substituted by one or more of cyclicalkyl, acyclic alkyl, alkene, alkyne, halogen, CN, OH, NH₂, NHR⁵, orOR⁵; or

phenyl, pyridine, pyridine N-oxide or heteroaryl, each of which isoptionally substituted by one or more of cyclic or acyclic alkyl,alkene, alkyne, OH, OMe, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, halogen,CN, CF₃, OCF₃, NHC(O)(C₁₋₆ alkyl), C(O)(C₁₋₆ alkyl), C(O)O(C₁₋₆ alkyl),OC(O)(C₁₋₆ alkyl), C(O)OH, C(O)NH(C₁₋₆ alkyl), C(O)N(C₁₋₆ alkyl)₂,S(C₁₋₆ alkyl), SO_(n)R⁶, NHS(O)_(n)(C₁₋₆ alkyl) where n is 1 or 2; or

an N-linked phenyl, pyridine, pyridine N-oxide or heteroaryl ring, eachof which is optionally substituted by one or more of cyclic or acyclicalkyl, alkene, alkyne, halogen, CN, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂,C(O)NH(C₁₋₆ alkyl), C(O)N(C₁₋₆ alkyl)₂, or C(O)O(C₁₋₆ alkyl).

In the above formula (1), R² may be H, an optionally substituted alkyl,cycloalkyl, aryl or heteroaryl, each of which is optionally linked toone or more C₁₋₆ alkyl, alkoxy, trifluoromethyl, carboxylalkyl, cyano,halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, or N-oxide. In someexamples, R² is phenyl, pyridiminyl, pyridinyl, thiazolyl, furanyl,thienyl, or imidazolyl.

In other embodiments, R² in formula (1) may be phenyl, pyridine orheteroaryl, each of which is optionally substituted by one or more ofcyclic or acyclic alkyl, alkene, alkyne, halogen, CN, NO₂, OH, NH₂, CF₃,CH₂OH, C(O)O(C₁₋₆ alkyl), OR⁷, or 5- or 6-membered non aromaticheterocyclic ring; or a C₁₋₆ alkyl, alkene or alkyne, OC(O)(C₁₋₆ alkyl),NHC(O)(C₁₋₆ alkyl), NHR⁸, or a 5- or 6-membered non aromaticheterocyclic ring.

In some embodiments, R¹ and R² are optionally substituted aryl orheteroaryl groups, which may be the same or different. In someembodiments, their substituents are selected from C₁₋₆ alkyl, halo, CN,CF₃, C₁-C₆ alkoxy, OH, NH₂, SH, C₁-C₆-alkylthio, or C₁₋₆ alkoxycarbonyl.

In the above formula (1), R³ may be H, OH, cyano, NR₂, SR, SOR, SO₂R,CO₂R, CONR₂, or an optionally substituted alkyl or alkoxy, wherein R isindependently H or C₁₋₆ alkyl; or R³ may be a carbocyclic ring, aheterocyclic ring, an aryl, or a heteroaryl, each of which may beoptionally substituted with halo, cyano, alkyl, alkoxy, cycloalkyl,heterocyclyl, aryl, heteroaryl, or N-oxide and/or fused with acarbocyclic, aryl, heterocyclic, or heteroaryl ring. In some examples,R³ is cyclohexyl, tetrahydropyran, morpholine, phenyl optionally fusedwith a 5-6 membered heterocyclic ring, pyridinyl, thienyl, C₁₋₆ straightor branched alkyl, bicyclo[4.2.0]octa-1,3,5-triene, indolyl,benzodioxolyl, dihydrobenzofuranyl, dihydroisobenzofuranyl,benzofuranyl, dihydrobenzodioxinyl, pyrrolidin-2-one, tetrazole,imidazole, dioxolane, or isoxazole.

In other embodiments, R³ is a cyclic or acyclic alkyl wherein one ormore carbons may be substituted with at least one heteroatom; or a 5- or6-membered non-aromatic ring, each of which is optionally substituted byone or more of cyclic alkyl acyclic alkyl, alkenyl, alkynyl, halogen,CN, OH, NH2, NHR⁵, or OR⁵; or

phenyl, pyridine, or heteroaryl, each of which is optionally substitutedby one or more of cyclic or acyclic alkyl, alkene, alkyne, halogen, CN,CHO, CF₃, OCF₃, NO₂, OH, NHC(O)(C₁₋₆ acyclic or C₃₋₆ cyclic alkyl),NHC(O)CF₃, NHSO₂(C₁₋₆ alkyl), NHC(O)NH₂, NHC(O)(C₁₋₆ alkyl), C(O)NH₂,C(O)NHC₆H₅, C(O)C₆H₄C(O)OH, C(O)N(OC₁₋₆ alkyl)(C₁₋₆ alkyl),C(O)NHCH₂C(O)O(C₁₋₆ alkyl), C(O)(C₁₋₆ alkyl), C(O)O(C₁₋₆ alkyl),C(O)(non-aromatic heterocylic ring), OC(O)(C₁₋₆ alkyl), O(C₁₋₆ alkyl),O(C₁₋₆ alkyl)O(C₁₋₆ alkyl), O(C₁₋₆ alkyl)C(O)OH, OC₆H₄C(O)OH,OC₆H₄C(O)NH₂, O(C₁₋₆ alkyl)C(O)O(C₁₋₆ alkyl), O(C₁₋₆ alkyl)C(O)NH₂,O(C₁₋₆ alkyl)C(O)NHNH₂, OSO₂(C₁₋₆ alkyl), OC(O)O(C₁₋₆ alkyl),OC(O)N(C₁₋₆ alkyl)₂, OC(O)(heteroaryl), COOH, C(O)NH(C₁₋₆ alkyl),C(O)N(C₁₋₆ alkyl)₂, S(C₁₋₆ alkyl), CH═NOH, CH═NO(C₁₋₆ alkyl), CH═N(C₁₋₆alkyl), (C₁₋₆ alkyl)C═NOH, (C₁₋₆ alkyl)C═NO(C₁₋₆ alkyl), (C₁₋₆alkyl)C═N(C₁₋₆ alkyl), (C₁₋₆ alkyl)C₆H₄C(O)OH, (C₁₋₆ alkyl)NHC(O)(C₁₋₆alkyl), CH═CHC(O)O(C₁₋₆ alkyl), CH═CHC(O)OH, SO_(n)R⁶ where n is 1 or 2;or phenyl, pyridine N-oxide, pyridine or heteroaryl each of which isoptionally substituted by one or more of alkyl, alkene, alkyne, halogen,CN, CF₃, OH, NH₂, OR⁷, (C₁₋₆ alkyl)R⁵, (C₁₋₆ alkene)R⁵, (C₁₋₆ alkyne)R⁵,or a 5- or 6-membered non aromatic heterocyclic ring;

or R³ can be phenyl, pyridinyl, thiazolyl, oxazolyl, pyrimidinyl,indolyl, indolinyl, isoindolinyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl,benzofuranyl, 2,3-dihydroxybenzofuranyl or phthalanyl, each of which isoptionally linked to one or more C₁₋₆ alkyl, trifluoromethyl,oxotrifluoromethyl, carboxylalkyl, cyano, halogen, sulfanyl, SO₂R⁹,where R⁹ is alkyl, amine or amino alkyl, C(O)R¹⁰, where R¹⁰ is alkyl,amine, morpholine, NMe₂, N(OMe)Me, NPh, piperidine, NHMe, piperazine,NHCH₂C(O)OMe or PhC(O)OH, OR¹¹, where R¹¹ is H, alkyl, (CH₂)₂OMe,CH₂C(O)NH₂, CH₂C(O)NHNH₂, CH₂C(O)OCMe₃, CH₂C(O)OMe, CH₂C(O)OH, PhC(O)OH,PhC(O)NH₂, SO₂Me, C(O)Me, C(O)OMe, C(O)NEt₂, C(O)NMe₂ or

NHR¹², where R¹² is H, C(O)Me, C(O)CF₃, SO₂Me, C(O)NH₂, C(O)NMe₂ or

NO₂, CH₂PhC(O)OH, SOMe, CH₂NHC(O)Me, morpholine, CH═CHC(O)OMe,CH═CHC(O)OH,

In the above formula (1), R⁴ may be H or C₁₋₆ alkyl.

In the above formula (1), R⁵ may be a C₁₋₆ alkyl, phenyl, pyridine,pyridine N-oxide or heteroaryl, each of which is optionally substitutedby one or more of C₁₋₆ alkyl, OH, OMe, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆alkyl)₂, halogen, CN, CF₃, OCF₃, C(O)NH(C₁₋₆ alkyl), C(O)N(C₁₋₆ alkyl)₂,C(O)O(C₁₋₆ alkyl), COOH, SO_(n)NH(C₁₋₆ alkyl), or SO_(n)(C₁₋₆ alkyl)where n is 1 or 2.

In the above formula (1), R⁶ may be C₁₋₆ alkyl, NH₂, NH(C₁₋₆ alkyl),N(C₁₋₆ alkyl)₂, or benzyl.

In the above formula (1), R⁷ may be a cyclic or acyclic alkyl, alkene,alkyne, phenyl, pyridine or heteroaryl, each of which is optionallysubstituted by one or more of C₁₋₆ alkyl, halogen, CN, NH₂, C(O)OH,C(O)O(C₁₋₆ alkyl), OH, SO_(n)NH₂ where n is 1 or 2, SO_(n)(C₁₋₆ alkyl)where n is 1 or 2, SO₂NH(C₁₋₆ alkyl), C(O)NH₂, C(O)NH(C₁₋₆ alkyl), orC(O)N(C₁₋₆ alkyl)₂; and R⁸ may be a C₁₋₆ alkyl, alkene or alkyne, OH, orOme.

In another aspect, the invention provides compounds having generalformula 2:

and pharmaceutically acceptable salts thereof;

wherein W is oxygen, sulfur, NR², NOR², NCN, NSO₂R², NAc, NNO₂, CRNO₂,NCOR², C(CN)₂ or CRCN;

V is O, S, N-L-R³, or CR-L-R³;

L is a bond or a (CR₂)_(m) linker optionally having one carbon of(CR₂)_(m) replaced by a group selected from O, S, and NR, and m is 1-3;

R¹ is an optionally substituted aryl or heteroaryl;

R² is H, an optionally substituted alkyl, a carbocyclic ring, aheterocyclic ring, an aryl, or a heteroaryl;

R³ is H; an optionally substituted alkyl, alkenyl or alkynyl; hydroxy,alkoxy, cyano, amino, amido, COR², CO₂R², S═(O)_(p)R², CR═N—OR,O(CR₂)CN, NR—COR², SR²; a carbocyclic ring, a heterocyclic ring, anaryl, or a heteroaryl; and

R is H, C₁₋₆ alkyl, or C₃₋₆ cycloalkyl;

wherein in each said optionally substituted alkyl, alkenyl or alkynyl, acarbon may be optionally substituted with halo, N, O, or S, and/orreplaced with N, O or S; and

each carbocyclic ring, heterocyclic ring, aryl or heteroaryl may beoptionally substituted and/or fused with a carbocyclic, aryl,heterocyclic, or heteroaryl ring.

In some embodiments of the compounds of formula (2), R¹ and R² areindependently an optionally substituted aryl or heteroaryl; R³ is H oran optionally substituted alkyl; or R³ is a carbocyclic ring, aheterocyclic ring, an aryl, or a heteroaryl, each of which may beoptionally substituted and/or fused with a carbocyclic, heterocyclic,aryl or heteroaryl ring; and each R is independently selected from H andC₁₋₆ alkyl.

In the above formula (2), R¹ may be phenyl, pyrimidinyl or pyridinyl,each optionally substituted with halo, cyano, alkyl, alkoxy, cycloalkyl,heterocyclyl, aryl, heteroaryl, or N-oxide.

In the above formula (2), R² may be phenyl, thienyl, or imidazolyl eachoptionally substituted with halo, cyano, alkoxy, heterocyclyl, aryl,heteroaryl, or N-oxide; or alkyl or cycloalkyl, each of which may beoptionally substituted with halo, cyano, OR, SR, or N(R)_(m), or inwhich one carbon may be optionally replaced with N, O, or S. In someexamples, R² is attached to the C that is attached to the nitrogen towhich the piperidine ring is linked. In other embodiments it is attachedto the ring carbon to which V is attached.

In the above formula (2), R³ may be a bond, H, C₁₋₁₀ straight orbranched alkyl; or R³ is a C₃₋₇ cycloalkyl, a 5-6 membered aryl,heteroaryl or heterocyclic ring, each optionally substituted with halo,cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, orfused with a carbocyclic or heterocyclic ring. In some compounds offormula (2), R³ is H, cyclopentyl, cyclohexyl, cycloheptyl,tetrahydropyran, morpholine, phenyl optionally fused to a 5-6 memberedheterocyclic ring, pyridinyl, imidazole, furan, pyrimidine, thienyl,C₁₋₆ straight or branched alkyl, or bicyclo[4.2.0]octa-1,3,5-triene.

Examples of heteroaryl substituents in the above formula (1) or (2)include but are not limited to pyridine, quinoline, isoquinoline,imidazole, benzimidazole, benzotriazole, furan, morpholine, benzofuran,dihydrobenzofuran, thiazole, benzothiazole, benzodioxole, benzodioxane,oxazole, isoxazole, benzoxazole, pyrrole, indole, indoline, isoindoline,indazole, pyrrolidine, pyrrolidone, tetrahydroquinoline,tetrahydroisoquinoline, pyrazole, thiophene, isothiazole, triazole,tetrazole, oxadiazole, thiadiazole, benzopyran, pyridazine, pyrimidine,pyrazine, 1,3,5-triazine, cinnoline, tetrahydrocinnoline, quinazoline,tetrahydroquinazoline, quinoxaline, tetrahydroquinoxaline, phthalan orphthalazine.

Where an alkyl, aryl or heteroaryl group in a compound of formula (1) or(2) is described as optionally substituted, unless otherwise described,it may comprise one or more substituents selected from those set forthfor R³ above. Suitable substituents for alkyl groups include, inaddition to those set forth above for R³, ═O, ═NOH, and ═NOR.

The present invention also relates to pharmaceutical compositionscomprising compounds of formula (1) or (2), in combination with at leastone pharmaceutically acceptable carrier. Furthermore, the presentinvention relates to methods for treating a CCR5 mediated disease in asystem, comprising contacting a compound of formula (1) or (2) with asystem (e.g., cell, tissue or organ), or administering a compound offormula (1) or (2) to a subject, which may be a human.

Examples of piperidine compounds having formula (1) include but are notlimited to the following compounds:

The present invention also relates to pharmaceutical compositionscomprising a piperidine derivative including but not limited tocompounds 1-303, and a pharmaceutically acceptable carrier. Furthermore,the present invention relates to methods for treating a CCR5 mediateddisease in a system, comprising contacting a piperidine derivative,including but not limited to compounds 1-303, with the system. In oneembodiment, the system is a cell or tissue. The present invention alsorelates to methods for treating a CCR5 mediated disease in a subject,comprising administering a piperidine derivative, including but notlimited to compounds 1-303, to the subject. The subject may be human oran animal.

Moreover, the compounds may be supplied as “pro-drugs” or protectedforms, which release the compound after administration to a subject. Theterms “administration” and or administering” as used herein should beunderstood to mean providing a compound of the invention to the subjectin need of treatment. For example, the compound may carry a protectivegroup which is split off by hydrolysis in body fluids, e.g., in thebloodstream, thus releasing the active compound or is oxidized orreduced in body fluids to release the compound. A discussion ofpro-drugs may be found in “Smith and Williams' Introduction to thePrinciples of Drug Design,” H.J. Smith, Wright, Second Edition, London(1988).

The compounds of the present invention may be administered in the formof pharmaceutically acceptable salts that are non-toxic. The term“pharmaceutically acceptable salt” as used herein means an activeingredient comprising compounds of Formula 1 or 2 used in the form of asalt thereof, particularly where the salt form confers on the activeingredient improved pharmacokinetic properties as compared to the freeform of the active ingredient or other previously disclosed salt form.The term “pharmaceutically acceptable salt” encompasses all acceptablesalts including but not limited to acetate, lactobionate,benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate,bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide,bromide, methylnitrate, calcium edetate, methylsulfate, camsylate,mucate, carbonate, napsylate, chloride, nitrate, clavulanate,N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate,edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate,esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate,polygalacturonate, gluconate, salicylate, glutame, stearate,glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydradamine,succinate, hydrobromide, tannate, hydrochloride, tartrate,hydroxynaphthoate, teoclate, iodide, tosylate, isothionate,triethiodide, lactate, panoate, valerate, and the like.

Pharmaceutically acceptable salts of the compounds of the presentinvention can be used as a dosage for modifying solubility or hydrolysischaracteristics, or can be used in sustained release or pro-drugformulations. Also, pharmaceutically acceptable salts of the compoundsof this invention may include those formed from cations such as sodium,potassium, aluminum, calcium, lithium, magnesium, zinc, and from basessuch as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine,ornithine, choline, N,N′-dibenzylethylene-diamine, chloroprocaine,diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine,piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammoniumhydroxide.

All of the compounds of the invention contain at least one chiralcenter. The invention includes mixtures of stereoisomers, individualstereoisomers, and enantiomeric mixtures, and mixtures of multiplestereoisomers. In short, the compound may be supplied in any desireddegree of chiral purity.

Utility and Administration

In one aspect, the invention is directed to compounds of Formula 1 or 2that may modulate chemokine receptor activity. Chemokine receptorsinclude but are not limited to CCR1, CCR2, CCR3, CCR4, CCR5, CXCR3, andCXCR4.

In one embodiment, the invention provides compounds of Formula 1 or 2that may demonstrate protective effects on target cells from HIVinfection by binding specifically to the chemokine receptor, thusaffecting the binding of a natural ligand to the CCR5 and/or CXCR4 of atarget cell.

In another embodiment, the compounds of the present invention may beuseful as agents which affect chemokine receptors, such as CCR1, CCR2,CCR3, CCR4, CCR5, CXCR3, CXCR4 where such chemokine receptors have beencorrelated as being important mediators of many inflammatory as well asimmunoregulatory diseases.

Other diseases that are also implicated with chemokines as mediatorsinclude angiogenesis, and tumorigenesis such as brain, and breasttumors. Thus, a compound that modulates the activity of such chemokinereceptors is useful for the treatment or prevention of such diseases.

As used herein, the terms “modulators and/or modulation” encompassantagonist/antagonism, agonist/agonism, partial antagonist/partialantagonism, and or partial agonist/partial agonism, i.e., inhibitors,and activators. The compounds of Formula 1 or 2 described herein maypossess biological activity such that they are able to modulate CCR5chemokine receptor activity and consequent or associated pathogenicprocesses subsequently mediated by the CCR5 receptor and its naturalligands.

In one embodiment, compounds of Formula 1 or 2 demonstrate a protectiveeffect against HIV infection by inhibiting the binding of HIV to achemokine receptor of a target cell such as CCR5 and/or CXCR4. Suchmodulation is obtained by a method which comprises contacting a targetcell with an effective amount of the compound to inhibit the binding ofthe virus to the chemokine receptor. As used herein, the terms“modulation and/or modulation” encompass modulating activity in alltypes and subtypes of CCR5 receptors of a target cell, in any tissues ofa particular patient where they are found, and in any cell componentscomprising those tissues that the target cell may be located.

Compounds that inhibit chemokine receptor activity and function may beused for the treatment of diseases that are associated withinflammation, including but not limited to, inflammatory or allergicdiseases such as asthma, allergic rhinitis, hypersensitivity lungdiseases, hypersensitivity pneumonitis, eosinophilic pneumonias,delayed-type hypersensitivity, atherosclerosis, interstitial lungdisease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associatedwith rheumatoid arthritis, systemic lupus erythematosus, ankylosingspondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis ordermatomyositis); systemic anaphylaxis or hypersensitivity responses,drug allergies, insect sting allergies; autoimmune diseases, such asrheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemiclupus erythematosus, myasthenia gravis, juvenile onset diabetes;glomerulonephritis, autoimmune thyroiditis, graft rejection, includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such as dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinophilic myotis, eosinophilic fascitis; and cancers.

In addition, compounds that activate or promote chemokine receptorfunction are used for the treatment of diseases associated withimmunosuppression, such as in individuals undergoing chemotherapy,radiation therapy, enhanced wound healing and burn treatment, therapyfor autoimmune disease or other drug therapy (e.g., corticosteroidtherapy) or combination of conventional drugs used in the treatment ofautoimmune diseases and graft/transplantation rejection, which causesimmunosuppression; or immunosuppression due to congenital deficiency inreceptor function or other causes. Compounds that activate or promotechemokine receptor function are also used for the treatment ofinfectious diseases, such as parasitic diseases, including but notlimited to helminth infections, such as nematodes (round worms);Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis,Trichinosis, filariasis; trematodes; visceral worms, visceral larvamigtrans (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisakispp., Phocanema ssp.), cutaneous larva migrans (Ancylostona braziliense,Ancylostoma caninum); the malaria-causing protozoan Plasmodium vivax,Human cytomegalovirus, Herpesvirus saimiri, and Kaposi's sarcomaherpesvirus, also known as human herpesvirus 8, and poxvirus Moluscumcontagiosum.

Compounds of the present invention may be used in combination with anyother active agents or pharmaceutical compositions where such combinedtherapy is useful to modulate chemokine receptor activity and therebyprevent and treat inflammatory and immunoregulatory diseases.

Furthermore, the compounds may be used in combination with one or moreagents useful in the prevention or treatment of HIV. Examples of suchagents include:

(1) nucleotide reverse transcriptase inhibitor such as tenofovirdisoproxil fumarate; lamivudine/zidovudine;abacavir/lamivudine/zidovudine; emtricitabine; amdoxovir; alovudine;DPC-817; SPD-756; SPD-754; GS7340; ACH-126,443 (beta)-L-F d4C;didanosine, zalcitabine, stavudine, adefovir, adefovir dipivoxil,fozivudine todoxil, etc.;

(2) non-nucleotide reverse transcriptase inhibitor (including an agenthaving anti-oxidation activity such as immunocal, oltipraz, etc.) suchas nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz,TMC-125; DPC-083; capravarine; calanolide A; SJ-3366 series, etc.;

(3) protease inhibitors such as saquinavir, lopinavir/ritonavir,atazanavir, fosamprenavir, tipranavir, TMC-114, DPC-684, indinavir,nelfinavir, amprenavir, palinavir, lasinavir, etc.;

(4) entry inhibitors such as T-20; T-1249; PRO-542; PRO-140; TNX-355;BMS-806 series; and 5-Helix;

(5) CCR5-receptor inhibitors such as Sch-C (or SCH351125); Sch-D (orSCH350634); TAK779; UK 427,857 and TAK 449; or CXCR4— receptorinhibitors such as T22, T134, T140, 18 amino acid analogs ofpolyphemusin II, ALX40-4C, ALK40-4C, AMD3100 and AMD070;

(6) Integrase inhibitors such as L-870,810; GW-810781 (S-1360); and

(7) Budding inhibitors such as PA-344; and PA-457.

Combinations of compounds of the present invention with HIV agents arenot limited to the above examples, but include the combination with anyagent useful for the treatment of HIV. Combinations the compounds of theinvention and other HIV agents may be administered separately or inconjunction. The administration of one agent may be prior to, concurrentto, or subsequent to the administration of other agent(s).

The compounds according to the present invention may be administered byoral, intramuscular, intraperitoneal, intravenous, intracisternalinjection or infusion, subcutaneous injection, transdermal ortransmucosal administration or by implant. They may also be administeredby inhalation spray, nasal, vaginal, rectal, sublingual, or topicalroutes and may be formulated, alone or together, in suitable dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles appropriate for each routeof administration.

The compounds of the invention may be used to treat animals, includingmice, rats, horses, cattle, sheep, dogs, cats, and monkeys. However,compounds of the invention can also be used in other species, such asavian species (e.g., chickens). The compounds of the invention may alsobe effective for use in humans. The term “subject” or alternativelyreferred to herein as “patient” is intended to be referred to an animal,preferably a mammal, most preferably a human, who has been the object oftreatment, observation or experiment. However, the compounds, methodsand pharmaceutical compositions of the present invention may be used inthe treatment of animals.

The invention also relates to a pharmaceutical composition comprising apharmaceutically acceptable carrier or diluent and an effective amountof compound of Formula 1 or 2. The compounds may be administered aloneor as a mixture with a pharmaceutically acceptable carrier (e.g., solidformulations such as tablets, capsules, granules, powders, etc.; liquidformulations such as syrups, injections, etc.). The compounds may beadministered orally or non-orally. Examples of non-oral formulationsinclude injections, drops, suppositories, pessaries.

In the treatment or prevention of conditions which require chemokinereceptor modulation, an appropriate dosage level will generally be about0.01 to 500 mg per kg subject body weight per day, and can beadministered in singe or multiple doses. Preferably, the dosage levelwill be about 0.1 to about 250 mg/kg per day. It will be understood thatthe specific dose level and frequency of dosage for any particularpatient may be varied and will depend upon a variety of factorsincluding the activity of the specific compound used, the metabolicstability and length of action of that compound, the age, body weight,general health, sex, diet, mode and time of administration, rate ofexcretion, drug combination, the severity of the particular condition,and the patient undergoing therapy.

In another aspect of the present invention, a compound of Formula 1 or 2may be used in screening assays for compounds which modulate theactivity of chemokine receptors, preferably CCR5 receptors. The abilityof a test compound to inhibit gp120 and CD4/CCR5-dependent cell-cellfusion may be measured using a cell fusion assay known in the art.

The compounds of Formula 1 or 2 as disclosed herein may be useful forisolating receptor mutants, which can then be made into screening toolsfor the discovery of even more potent compounds, following proceduresdescribed herein and procedures known in the art. The compounds ofFormula 1 or 2 may also be useful in establishing or characterizing thebinding sites of other ligands, including compounds other than those ofFormula 1 or 2 to chemokine receptors, e.g., by competitive inhibition.The compounds of the present invention may also be useful for theevaluation of putative specific modulators of various chemokinereceptors. As appreciated in the art, thorough evaluation of specificagonists and antagonists of the above chemokine receptors has beenhampered by the lack of availability of non-peptidyl (metabolicallyresistant) compounds with high binding affinity for these receptors.Thus, the compounds of this invention are commercial products to be soldfor these purposes.

The invention is further described by means of examples, but not in anylimitative sense.

EXPERIMENTAL

Compounds of the invention are often readily prepared by known methods;some methods for making compounds and intermediates of the invention aredescribed in a co-pending application by Bridger, et al., which isInternational Patent Application No. PCT/US2004/041865.

General Procedures

General procedure A: Reductive Amination with NaBH(OAc)₃

To a stirred solution of the amine (1 equivalent) in CH₂Cl₂(concentration ˜0.2M) at room temperature were added the carbonylcompound (1-2 equivalents), glacial AcOH (0-2 equivalents) and sodiumtriacetoxyborohydride (NaBH(OAc)₃) (˜1.5-3 equivalents) and theresultant solution was stirred at room temperature. In a standardworkup, the reaction mixture was poured into either saturated aqueousNaHCO₃ or 1N NaOH. The phases were separated and the aqueous extractedwith CH₂Cl₂. The combined organic extracts were dried (Na₂SO₄ or mgSO₄),filtered and concentrated under reduced pressure. The crude material waspurified by flash column chromatography on silica gel or byrecrystallization.

General Procedure B: Reductive Amination with NaCNBH₃

To a stirred solution of the amine (1 equivalent) in MeOH (concentration˜0.1M) at room temperature were added the carbonyl compound (1-3equivalents), glacial AcOH (0-1 equivalents) and sodium cyanoborohydride(NaCNBH₃) (˜1.5-3 equivalents) and the resultant solution was heated toreflux. In a standard workup, the reaction mixture was concentratedunder reduced pressure and diluted with saturated aqueous NaHCO₃. Theaqueous was extracted with CH₂Cl₂ and the combined organic extracts weredried (Na₂SO₄ or mgSO₄), filtered and concentrated under reducedpressure. The crude material was purified by flash column chromatographyon silica gel or by recrystallization.

General Procedure C: BOC Deprotection with TFA

The BOC-protected amine was dissolved in CH₂Cl₂ (˜4 ml/mmol) andtrifluoroacetic acid (TFA) (˜2 ml/mmol) was added. The mixture wasstirred at room temperature for 0.5-5 hours. In a standard work-up, themixture was neutralized with saturated aqueous NaHCO₃ or 1N NaOH and theaqueous extracted with CH₂Cl₂. The combined extracts were dried (Na₂SO₄or mgSO₄), filtered and concentrated under reduced pressure. The crudematerial was used in the next reaction as is or was purified by flashcolumn chromatography on silica gel.

General Procedure D: Phthalimide Deprotection

To a solution of the phthalimide-protected amine in EtOH (0.05-0.2M) wasadded hydrazine hydrate (˜10 equivalents). The resulting mixture wasstirred at room temperature overnight or heated at 40-50° C. for 2-16hours. In a standard work-up, the mixture was concentrated under reducedpressure, diluted with CH₂Cl₂ and filtered. The filtrate wasconcentrated under reduced pressure and purified by flash columnchromatography on silica gel.

General Procedure E: EDCI Coupling

To a stirred solution of a primary or secondary amine (1 equivalent), acarboxylic acid (1.1-2.0 equivalents), 1-hydroxy-benzotriazole hydrate(HOBT) (1.1-2.0 equivalents) and diisopropylethylamine (DIPEA) orN-methylmorpholine (NMM) (1.5-3 equivalents) in CH₂Cl₂ or DMF(concentration ˜0.05-1.5M) was added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI)(1.1-2.0 equivalents). The solution was stirred at room temperature for1-3 days and concentrated in vacuo. In a standard work-up, the mixturewas diluted with CH₂Cl₂ or EtOAc and washed consecutively with saturatedaqueous NaHCO₃ and brine. The organic layer was dried (Na₂SO₄ or mgSO₄),filtered and concentrated under reduced pressure. The crude material waspurified by flash column chromatography or by radial chromatography onsilica gel.

General Procedure F: Formation of Thioamide with Lawesson's Reagent

A solution of amide (concentration ˜0.1 mmol, 1 eq.) and Lawesson'sreagent (1 eq.) in toluene was refluxed for 2.5 h. The toluene wasremoved and the residual material was purified on silica gel column (5%ether in CH₂Cl₂) to afford the desired product.

General Procedure G: Coupling with Acid Chloride

To a solution of the amine (1 equiv) and DIPEA (2 equiv) in dry CH₂Cl₂(concentration 0.05-0.2 M) was added the acid chloride (1.2-1.5 equiv),and the resulting mixture was stirred overnight. The crude mixture wasdiluted with saturated aqueous NaHCO₃ and the aqueous layer wasextracted with CH₂Cl₂. The combined organic extracts were washed withbrine, dried (Na₂SO₄ or mgSO₄) and purified by flash chromatography onsilica gel.

General Procedure H: Formation of Ureas with Isocyanates

To a solution of the amine (1 equiv) in dry CH₂Cl₂ (concentration0.05-0.2 M) was added the isocyanate (1.2-1.5 equiv), and the resultingmixture was stirred overnight. The crude mixture was diluted withsaturated aqueous NaHCO₃ and the aqueous layer was extracted withCH₂Cl₂. The combined organic extracts were washed with brine, dried(Na₂SO₄ or mgSO₄) and purified by flash chromatography on silica gel.

General Procedure I: Formation of Ureas with CDI

To a solution of the primary amine (or the HCl salt of the primaryamine) (4 equiv) and DIPEA (4 equiv) in dry acetonitrile or1,2-dichloroethane (concentration 0.1-0.5 M) was addedcarbonyldiimidazole (CDI) (4 equiv) and the resulting mixture wasstirred at 60° C. for 2 h. At this point, the secondary amine (1 equiv)was added, and stirring was continued at 60° C. overnight. The crudemixture was concentrated, and then the residue was diluted withsaturated aqueous NaHCO₃ and extracted with CH₂Cl₂. The combined organicextracts were washed with brine, dried (Na₂SO₄ or mgSO₄) and purified byflash chromatography on silica gel.

General Procedure J: Coupling with Phenyl Carbamate

To a solution of the phenylcarbamate (or the p-nitrophenylcarbamate)(1.25-2.0 equiv) and DIPEA (1.5-2.0 equiv) in dry THF or1,2-dichloroethane (concentration 0.05-0.2 M) was added the secondaryamine (1 equiv). The resulting mixture was stirred at 60-70° C.overnight, at which time the reaction was diluted with saturated aqueousNaHCO₃ and extracted with CH₂Cl₂. The combined organic extracts werewashed with brine, dried (Na₂SO₄ or mgSO₄) and purified by flashchromatography on silica gel.

Intermediates

2,6-Dimethyl-N-[3-(4-oxo-piperidin-1-yl)-butyl]-benzamide

To a solution of 1,4-dioxa-8-azaspiro[4.5]decane (8.00 g, 55.9 mmol) inMeOH (70 ml) was added crotononitrile (18.74 g, 279 mol). The mixturewas heated at 50° C. for 16 hours. MeOH and excess crotononitrile wereremoved by evaporation under reduced pressure to give3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butyronitrile (11.75 g, 100%) asa pale yellow oil.

To a solution of 3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butyronitrile(2.80 g, 13.3 mmol), in MeOH (50 ml) was added Raney Ni (˜5 ml). Themixture was hydrogenated at 50 psi at rt for 1.5 hours. The catalyst wasremoved by filtration through a layer of Celite® and the solvents wereevaporated to give the crude product as a colorless oil (2.85 g, 100%).

Using general procedure E with3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butylamine (2.30 g, 10.7 mmol)and 2,6-dimethylbenzoic acid (1.77 g, 11.8 mmol) followed bypurification by column chromatography on silica gel (1-5% MeOH/CH₂Cl₂)gaveN-[3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butyl]-2,6-dimethyl-benzamide(3.11 g, 83%).

A solution ofN-[3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-butyl]-2,4-dimethyl-1-benzamide(3.11 mg, 8.95 mmol) in acetone (10 ml) and HCl 6N (aq, 8 ml) wasrefluxed for 18 h. The reaction mixture was quenched with NaOH (aq, 15%)to pH 7-8. The organic material was extracted with CH₂Cl₂ and theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography on silica gel (10% MeOH inCH₂Cl₂; 2.5% NH₄OH) to afford2,4-dimethyl-N-[3-(4-oxo-piperidin-1-yl)butyl]-1-benzamide (543 mg,22%). ¹H NMR (CDCl₃) δ 1.00 (d, 3H, J=6.6 Hz), 1.57-1.67 (m, 1H),1.73-1.83 (m, 1H), 2.12-2.28 (m, 4H), 2.31 (s, 6H), 2.60-2.68 (m, 2H),2.84-2.97 (m, 3H), 3.42-3.50 (m, 1H), 3.69-3.79 (m, 1H), 6.98 (d, 2H,J=7.5 Hz), 7.11 (t, 1H, J=7.5 Hz), 7.20 (br s, 1H).

4,6-Dimethyl-pyrimidine-5-carboxylic acid[3-(4-oxo-piperidin-1-yl)-butyl]-amide

Using general procedure E with3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butylamine (4.50 g, 21.0 mmol)and 4,6-dimethyl-pyrimidine-5-carboxylic acid (3.20 g, 21.0 mmol),followed by purification by column chromatography on silica gel (2-10%MeOH/CH₂Cl₂) gave 4,6-dimethyl-pyrimidine-5-carboxylic acid[3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butyl]-amide (5.10 g, 73%).

A solution of 4,6-dimethyl-pyrimidine-5-carboxylic acid[3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butyl]-amide (3.11 g, 8.95 mmol)in acetone (10 ml) and HCl 6N (aq, 8 ml) was refluxed for 18 h. Thereaction mixture was quenched with NaOH (aq, 15%) to pH 7-8. The organicmaterial was extracted with CH₂Cl₂ and the organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography on silica gel (10% MeOH in CH₂Cl₂; 2.5% NH₄OH) to afford4,6-dimethyl-pyrimidine-5-carboxylic acid[3-(4-oxo-piperidin-1-yl)-butyl]-amide (589 mg, 23%). ¹H NMR (CDCl₃) δ1.04 (d, 3H, J=6.6 Hz), 1.64-1.72 (m, 1H), 1.81-1.91 (m, 1H), 2.15-2.30(m, 4H), 2.52 (s, 6H), 2.62-2.72 (m, 2H), 2.84-2.98 (m, 3H), 3.47-3.62(m, 1H), 3.69-3.77 (m, 1H), 6.94 (br s, 1H), 8.93 (s, 1H).

2,4-Dimethyl-N-[3-(4-oxo-piperidin-1-yl)-butyl]-1-oxy-nicotinamide

Using general procedure E with3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butylamine (4.50 g, 21.0 mmol)and 2,4-dimethyl-1-oxy-nicotinic acid (3.20 g, 21.0 mmol), followed bypurification by column chromatography on silica gel (2-10%MeOH/CH₂Cl₂)gave 4,6-dimethyl-N—O pyridine-5-carboxylic acid[3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butyl]-amide (5.3 g, 73%).

A solution 4,6-dimethyl-N—O pyridine-5-carboxylic acid[3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butyl]-amide (3.11 mg, 8.95mmol) in acetone (10 ml) and HCl 6N (aq, 8 ml) was refluxed for 18 h.The reaction mixture was quenched with NaOH (aq, 15%) to pH 7-8. Organicmaterial was extracted with CH₂Cl₂ and the organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography on silica gel (10% MeOH in CH₂Cl₂; 2.5% NH₄OH) to afford2,4-dimethyl-N-[3-(4-oxo-piperidin-1-yl)-butyl]-1-oxy-nicotinamide (533mg, 24%). ¹H NMR (CDCl₃) δ 0.96-1.05 (m, 2H), 1.04 (d, 3H, J=6.6 Hz),1.50-1.97 (m, 3H), 2.31 (s, 3H), 2.33 (m, 3H), 2.32-2.50 (m, 2H),2.63-2.75 (m, 2H), 2.85-3.05 (m, 2H), 3.58 (q, 2H, J=5.7 Hz), 6.89 (d,1H, J=6.6 Hz), 7.85 (d, 1H, J=6.6 Hz), 8.51-8.53 (m, 1H).

(R)-3-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-4-phenyl-oxazolidine-2-thione

Using general procedure A, R-phenylglycinyl ((2.85 g, 0.02 mol) and (R,S)-[3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester (5.0g, 0.0185 mol) gave the desired amine as a light yellow foam solid (7.6g, 95%), which was used in the next step without purification.

To a solution of the above substrate (7.6 g, 0.019 mol) in DMF (50 ml)was added 1,1′-thiocarbonyldiimidazole (3.46 g, 0.0194 mol). The mixturestirred at rt for 16 hrs at which point only 35% conversion hadoccurred. 1,1′-Thiocarbonyldiimidazole (5.2 g, 0.029 mol) was added tothe mixture and the reaction was complete by 5 hrs. The reaction wasquenched with saturated aqueous NaHCO₃ and extracted with EtOAc. Theorganic layer was dried with mgSO₄ and the crude material was purifiedby a column chromatography to afforded (R,S)-3-[1-(3-amino-1-methyl-propyl)-piperidine-4-yl]-4-phenyl-oxazolidine-2-thione-1-carboxylicacid tert-butyl ester (5.45 g, 65%).

Using general procedure C the substrate (5.0 g, 0.012 mol) gave thedesired amine. Due to the high water solubility of the compound, themixture was neutralized with solid K₂CO₃ and the product was purified bycolumn chromatography to afford(R,S)-3-[1-(3-amino-1-methyl-propyl)-piperidine-4-yl]-4-phenyl-oxazolidine-2-thione(1.6 g, 42%). ¹H NMR (CDCl₃) δ 0.90 (d, 3H), 0.90-1.0 (m, 1H), 1.31-1.91(m, 8H), 2.03-2.05 (m, 1H), 2.61-2.75 (m, 6H), 4.32-4.36 (m, 2H),4.94-4.98 (m, 1H), 5.29 (d, 1H), 7.25-7.42 (m, 5H).

2,6-Dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide

To a solution of((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (3.01 g, 8.19 mmol) in THF (10 ml) was added 6 NHCl (10 ml) and the reaction stirred at 50° C. for 2 then at rt for 1 h.The mixture was concentrated, diluted with CH₂Cl₂ (50 ml) and 10 N NaOH(10 ml) and the aqueous layer extracted with CH₂Cl₂ (3×25 ml). Thecombined organic extracts were dried (Na₂SO₄) and concentrated to affordthe deprotected material (1.88 g, 86%) as a yellow oil.

Following general procedure E: to a solution of the amine from above(1.88 g, 7.03 mmol) in CH₂Cl₂ (25 ml) was added2,6-dichloro-4-methyl-nicotinic acid (1.5927 g, 7.73 mmol), HOBt (1.055g, 7.81 mmol), DIPEA (1.3 ml, 7.48 mmol) and EDCI (1.5371 g, 8.02 mmol)and the reaction stirred overnight. Purification of the crude product bycolumn chromatography through a plug of silica gel (CH₂Cl₂/MeOH/NH₄OH,96:4:0 then 9:1:0 then 88:10:2) afforded the desired intermediate (2.42g, 65% over 2 steps) as a yellow foam. ¹H NMR (CDCl₃) δ 0.78-0.95 (m,1H), 0.97-1.05 (m, 1H), 0.98 (d, 3H, J=6.6 Hz), 1.51-1.58 (m, 1H),1.79-1.83 (m, 3H), 2.11-2.14 (m, 1H), 2.35 (s, 3H), 2.43-2.49 (m, 2H),2.70-2.88 (m, 3H), 3.33-3.42 (m, 1H), 3.71 (s, 2H), 3.73-3.78 (m, 1H),7.00 (d, 1H, J=4.8 Hz), 7.09 (d, 1H, J=3 Hz), 7.12 (s, 1H), 7.26 (dd,1H, J=4.8, 3 Hz), 8.85 (br s, 1H).

Examples 1 to 37 were prepared following the scheme illustrated below.R¹ is as defined in the individual examples and R²COOH is as defined inthe table.

TABLE 1

Example R²COOH  1* (4,4-difluorocyclohexyl)-acetic acid  2*3-cyclohexyl-propionic acid  3* 4-pyridylthioacetic acid  4*1-benzocyclobutenecarboxylic acid  5* 3-thiopheneacetic acid  6*(pyridin-2-ylsulfanyl)-acetic acid  7*(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-acetic acid  8*(1-methyl-1H-imidazol-2-ylsulfanyl)-acetic acid  9*(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-acetic acid 102-(2-methoxyethoxy)acetic acid 11 3-methyl-5-isoxazoleacetic acid 12morpholin-4-yl-acetic acid 13 pyridin-2-yl-acetic acid hydrochloride 14pyridin-3-yl-acetic acid hydrochloride 15 pyridin-4-yl-acetic acidhydrochloride 16 3-methoxypropionic acid 17 tetrazol-1-ylacetic acid 18(2-oxo-pyrrolidin-1-yl)-acetic acid 19 hippuric acid 20imidazol-1-yl-acetic acid 21 hydantoic acid 22 N,N-dimethyl glycine 23methane sulphonyl acetic acid 24 (2-oxo-oxazolidin-3-yl)-acetic acid 25acrylic acid 26 N-acetyl-beta-alanine 27 1,2,4-triazole-1-acetic acid 281-pyrrolidineacetic acid 29 3,3-dimethylacrylic acid 302-oxo-1-pyrrolidineacetic acid 31 1H-tetrazole-1-acetic acid 32cyanoacetic acid 33 (2-oxo-oxazolidin-3-yl)-acetic acid (see COMPOUND24) 34 methoxyiminoacetic acid (Graf, H. et al. Eur. Pat. Appl. (1983)EP 0088325) 35 1-cyano-cyclopropanecarboxylic acid 36(2-oxo-imidazolidin-1-yl)-acetic acid 37 cyclopropylacetic acid *=racemic

Example 1

Compound 1 4,6-Dimethylpyrimidine-5-carboxylic acid[3-(4-{[2-(4,4-difluorocyclohexyl)-acetyl]-thiophen-3-ylmethylamino}-piperidin-1-yl)-butyl]-amide

White solid. ¹H NMR (CDCl₃) mixture of rotomers: δ 0.77-1.48 (m, 9H),1.49-2.45 (m, 13H), 2.48-2.59 (m, 6H), 2.63-2.93 (m, 3H), 3.24-3.46 (m,1H), 3.73-4.09 (m, 3H), 4.39-4.56 (m, 1H), 6.96 (m, 2H), 7.31-7.38 (m,1H), 7.86-7.94 and 8.59-8.75 (m, 1H), 8.89-8.95 (m, 1H); ¹³C NMR (CDCl₃)δ 13.8, 22.4, 29.2, 29.3, 29.6, 30.1, 30.9, 31.7, 33.2, 33.5, 33.8,34.1, 39.8, 40.8, 43.0, 43.8, 44.2, 51.6, 52.2, 56.1, 60.1, 60.8, 121.0,121.6, 123.8, 125.9, 126.2, 127.3, 127.8, 140.0, 157.9, 158.2, 163.5,172.6; ES-MS m/z 562 (M+H). Anal. Calcd. forC₂₉H₄₁N₅F₂O₂S·0.5C₄H₁₀·0.1CH₂Cl₂: C, 61.51; H, 7.67; N, 11.53. Found: C,61.44; H, 7.58; N, 11.56.

Example 2

Compound 2 4,6-Dimethyl-pyrimidine-5-carboxylic acid(3-{4-[(3-cyclohexyl-propionyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide

White solid. ¹H NMR (CDCl₃) δ 0.70-1.30 (m, 12H), 1.31-2.80 (m, 12H),2.05-2.80 (m, 13H), 3.20-4.55 (m, 5H), 6.86-7.30 (m, 3H), 7.95 (br s,0.25H), 8.74 (s, 0.75H), 8.87 (s, 0.75H), 8.90 (s, 0.25H); ¹³C NMR(CDCl₃) δ 13.81, 22.30, 26.60, 26.90, 30.89, 31.39, 31.57, 31.79, 32.22,33.20, 37.70, 39.89, 40.51, 40.65, 43.01, 43.74, 44.34, 51.50, 52.16,56.25, 59.87, 60.75, 120.85, 121.54, 125.64, 126.24, 127.00, 127.81,131.07, 131.34, 140.40, 140.75, 157.87, 158.09, 163.49, 166.62, 166.86,173.41, 174.51; ES-MS m/z 540 (M+H). Anal. Calcd. forC₃₀H₄₅N₅O₂S·1.3CH₂Cl₂: C, 65.15; H, 8.22; N, 12.58; S, 5.76. Found: C,65.40; H, 8.26; N, 12.48, S, 5.71.

Example 3

Compound 3 4,6-Dimethyl-pyrimidine-5-carboxylic acid(3-{4-{[2-(pyridin-4-ylsulfanyl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl}-butyl]-amide

¹H NMR (CDCl₃) δ 0.76-1.80 (m, 11H), 1.99-2.25 (m, 3H), 2.40-2.80 (m,11H), 3.25-4.50 (m, 8H), 6.75-7.50 (m, 5H), 7.78 (br s, 2H), 7.25-7.49(m, 2H), 8.52 (br s, 0.8H), 8.83 (s, 0.8H), 8.90 (br s, 0.2H); ¹³C NMR(CDCl₃) δ 13.84, 22.32, 29.87, 30.72, 31.13, 31.37, 32.11, 34.48, 34.84,39.73, 40.33, 41.26, 43.48, 43.74, 44.30, 51.95, 52.68, 57.48, 59.63,60.50, 121.37, 121.50, 121.85, 126.12, 127.50, 127.92, 131.28, 139.21,148.08, 149.66, 149.84, 157.88, 158.08, 163.48, 166.66, 168.34; ES-MSm/z 553 (M+H). Anal. Calcd. for C₂₈H₃₆N₆O₂S₂·0.2CH₂Cl₂: C, 59.45; H,6.44; N, 14.75. Found: C, 59.34; H, 6.57; N, 14.71.

Example 4

Compound 4 4,6-Dimethyl-pyrimidine-5-carboxylic acid(3-{-4-[(bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide

White solid. ¹H NMR (CDCl₃) mixture of rotomers: δ 0.80-1.37 (m, 8H),1.38-3.00 (m, 8H), 2.53 and 2.55 (s, 6H), 3.01-4.48 (m, 6H), 6.83-7.47(m, 7H), 7.80 and 8.72 (s, 1H), 8.84-8.93 (s, 1H); ¹³C NMR (CDCl₃) δ13.8, 22.4, 29.8, 30.9, 31.7, 31.9, 32.5, 34.1, 34.2, 34.5, 34.7, 40.0,40.5, 41.0, 43.0, 43.8, 44.2, 45.8, 46.1, 52.2, 55.9, 60.0, 60.1, 60.8,122.6, 123.8, 125.4, 126.4, 127.3, 127.5, 128.4, 128.6, 140.2, 143.9,144.5, 158.0, 158.2, 163.6, 172.7; ES-MS m/z 532 (M+H). Anal. Calcd. forC₃₀H₃₇N₅O₂S·0.4CH₂Cl₂·0.5C₄H₁₀O: C, 64.56; H, 7.16; N, 11.62. Found: C,64.94; H, 7.01; N, 11.58.

Example 5

Compound 5 4,6-Dimethyl-pyrimidine-5-carboxylic acid(3-{4-[(2-thiophen-3-yl-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide

White solid. ¹H NMR (CDCl₃) δ 0.75-1.10 (m, 4H), 1.25-2.79 (m, 15H),3.25-4.50 (m, 6H), 6.93-7.45 (m, 6H), 7.97 (br s, 0.25H), 8.59 (br s,0.75H), 8.80 (s, 0.75H), 8.89 (s, 0.25H); ¹³C NMR (CDCl₃) δ 11.99,20.50, 28.02, 28.91, 29.20, 29.39, 29.87, 30.23, 31.08, 34.49, 35.21,36.70, 38.08, 38.58, 39.03, 41.50, 41.92, 42.47, 43.24, 50.14, 50.26,55.08, 58.04, 58.78, 119.22, 119.91, 120.52, 123.94, 124.38, 124.62,124.83, 125.48, 125.98, 126.56, 126.75, 129.44, 133.22, 133.50, 138.28,138.43, 156.06, 156.27, 161.63, 164.85, 165.00, 168.89, 169.89; ES-MSm/z 526 (M+H). Anal. Calcd. for C₂₇H₃₅N₅S₂O₂·0.3CH₄O: C, 59.49; H, 6.51;N, 12.71. Found: C, 59.43; H, 6.49; N, 12.82.

Example 6

Compound 6 4,6-Dimethyl-pyrimidine-5-carboxylic acid[3-(4-{[2-(pyridin-2-ylsulfanyl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide

A solution of 2-mercaptopyridine (484 mg, 4.35 mmol), methylbromoacetate (0.45 ml, 4.8 mmol), and Et₃N (0.79 ml, 5.7 mmol) in CH₃CN(22 ml) was stirred at room temperature for 20 h to give(pyridin-2-ylsulfanyl)-acetic acid methyl ester as a colorless oil (752mg, 94%) after aqueous work-up and purification.

A solution of the ester from above (751 mg, 4.10 mmol) in MeOH (50 ml)and 1N NaOH (10 ml) was stirred at room temperature for 45 minutes togive (pyridin-2-ylsulfanyl)-acetic acid (655 mg, 95%) after acidicwork-up.

COMPOUND 6 was isolated as a yellow foam (2:1 mixture of rotamers). ¹HNMR (CDCl₃) δ 0.87-1.93 (m, 19H), 2.09-2.29 (m, 2H), 2.51-2.79 (m, 19H),3.30 (m, 2H), 3.69-4.22 (m, 11H), 4.44 (m, 1H), 6.92-7.12 (m, 6H),7.17-7.28 (m, 3H), 7.34 (dd, 1H, J=4.8, 3.0 Hz), 7.43-7.53 (m, 2H), 8.05(br s, 1H), 8.35 (d, 1H, J=4.5 Hz), 8.39 (d, 1H, J=4.5 Hz), 8.73 (m,1H), 8.88 (s, 1H), 8.93 (s, 1H); ¹³C NMR (CDCl₃) δ 13.32, 13.44, 21.95,29.34, 30.28, 30.52, 30.91, 31.21, 31.78, 32.00, 32.98, 39.65, 40.13,40.78, 43.09, 43.29, 43.41, 51.52, 51.72, 52.05, 56.01, 59.65, 60.36,119.68, 119.97, 120.86, 121.17, 121.96, 122.40, 125.34, 126.01, 126.73,127.25, 130.71, 130.95, 136.00, 136.42, 139.60, 139.73, 149.07, 156.99,157.55, 157.72, 163.12, 166.28, 166.43, 168.86, 169.63; ES-MS m/z 553(M+H). Anal. Calcd. for C₂₈H₃₆N₆S₂O₂·0.5CH₄O: C, 60.18; H, 6.73; N,14.78; S, 11.27. Found: C, 60.24; H, 6.44; N, 14.54; S, 11.10.

Example 7

Compound 7 4,6-Dimethyl-pyrimidine-5-carboxylic acid[3-(4-{[2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide

Colorless foam (2:1 mixture of rotamers). ¹H NMR (CDCl₃) δ 0.90-1.80 (m,18H), 2.14 (m, 2H), 2.53 (m, 14H), 2.67-2.82 (m, 12H), 3.34 (m, 2H),3.64-3.85 (m, 3H), 4.02-4.26 (m, 6H), 4.39 (m, 3H), 6.94 (d, 1H, J=4.8Hz), 7.02 (m, 2H), 7.11 (m, 1H), 7.21 (dd, 1H, J=5.0, 3.2 Hz), 7.36 (dd,1H, J=4.8, 3.0 Hz), 7.89 (br s, 1H), 8.48 (br s, 1H), 8.87 (s, 1H), 8.93(s, 1H); ¹³C NMR (CDCl₃) δ 13.83, 13.92, 15.96, 22.30, 29.84, 30.68,31.23, 31.84, 32.08, 37.95, 39.75, 40.18, 41.32, 43.71, 43.83, 44.11,51.62, 51.89, 53.05, 57.01, 59.63, 60.26, 121.45, 122.07, 125.96,126.23, 127.56, 127.68, 131.07, 131.18, 139.17, 139.46, 157.90, 158.00,163.41, 164.88, 165.14, 165.60, 165.71, 166.72, 166.84, 166.94, 167.85;ES-MS m/z 574 (M+H). Anal. Calcd. for C₂₆H₃₅N₇S₃O₂·0.2CH₂Cl₂: C, 53.27;H, 6.04; N, 16.60; S, 16.28. Found: C, 53.34; H, 6.15; N, 16.57; S,16.17.

Example 8

Compound 8 4,6-Dimethyl-pyrimidine-5-carboxylic acid[3-(4-{[2-(1-methyl-1H-imidazol-2-ylsulfanyl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide

Colorless foam (2:1 mixture of rotamers). ¹H NMR (CDCl₃) δ 0.81-1.35 (m,10H), 1.48-1.80 (m, 8H), 2.11 (m, 2H), 2.47 (m, 14H), 2.64-2.79 (m, 6H),3.31 (m, 2H), 3.56-3.83 (m, 11H), 3.94-4.19 (m, 6H), 4.35 (m, 1H), 6.90(m, 3H), 6.99 (m, 5H), 7.19 (dd, 1H, J=5.1, 3.0 Hz), 7.32 (dd, 1H,J=5.0, 3.2 Hz), 8.02 (br s, 1H), 8.53 (m, 1H), 8.88 (s, 1H), 8.91 (s,1H); ¹³C NMR (CDCl₃) δ 13.82, 13.90, 22.30, 29.74, 30.62, 31.11, 31.33,31.66, 32.12, 33.73, 33.79, 37.54, 37.72, 39.89, 40.27, 41.15, 43.42,43.76, 43.92, 51.62, 51.92, 52.52, 56.71, 59.84, 60.39, 121.13, 121.97,122.99, 123.06, 125.76, 126.23, 127.30, 127.74, 129.61, 129.74, 131.11,131.21, 139.64, 140.57, 140.91, 157.93, 158.01, 163.40, 166.70, 166.80,168.22, 169.05; ES-MS m/z 556 (M+H). Anal. Calcd. forC₂₇H₃₇N₇S₂O₂·0.2CH₂Cl₂: C, 57.04; H, 6.58; N, 17.12; S, 11.20. Found: C,56.77; H, 6.65; N, 16.97; S, 11.10.

Example 9

Compound 9 4,6-Dimethyl-pyrimidine-5-carboxylic acid[3-(4-{[2-(pyridin-3-ylsulfanyl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide

White foam (mixture of rotamers). ¹H NMR (CDCl₃) δ 0.85-1.80 (m, 9H),2.10 (m, 1H), 2.30-2.80 (m, 9H), 3.25-4.45 (m, 8H), 3.34 (m, 2H),6.94-8.95 (m, 9H); ¹³C NMR (CDCl₃) δ 13.81, 22.34, 29.82, 30.70, 31.01,31.37, 31.83, 32.16, 37.27, 37.80, 39.88, 40.42, 41.08, 43.30, 43.65,44.19, 51.98, 52.35, 57.33, 59.84, 60.62, 121.46, 121.99, 124.09,124.30, 125.91, 126.08, 127.72, 131.28, 132.24, 138.47, 139.05, 139.39,148.62, 151.15, 151.79, 157.92, 158.11, 163.49, 166.65, 168.82; ES-MSm/z 554.0 (M+2). Anal. Calcd. for C₂₈H₃₆N₆S₂O₂·0.6CH₂Cl₂: C, 56.90; H,6.21; N, 13.92. Found: C, 57.00; H, 6.41; N, 13.88.

Example 10

Compound 102,6-Dichloro-N—[(R)-3-(4-{[2-(2-methoxy-ethoxy)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-4-methyl-nicotinamide

¹H NMR (CDCl₃) (mixture of rotamers) δ 0.97 (d+m, 4H), 1.24 (m, 1H),1.41-1.76 (m, 5H), 2.14 (m, 1H), 2.35 (s+m, 4H), 2.53 (br t, 1H),2.74-2.84 (m, 3H), 3.35 (s+m, 4H), 3.53 (s, 2H), 3.65 (s, 3H), 3.76 (m,1H), 4.03-4.08 (m, 3H), 4.23-4.35 (m, 1H), 6.97 (d, 1H, J=3.0 Hz), 7.02(s, 1H), 7.11 (s, 1H), 7.20 (s) and 7.32 (s) (total 1H), 8.24 (br s) and8.72 (br s) (total 1H); ES-MS m/z 571 (M+H).

Example 11

Compound 112,6-Dichloro-4-methyl-N—[(R)-3-(4-{[2-(3-methyl-isoxazol-5-yl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-nicotinamide

¹H NMR (CDCl₃) (mixture of rotamers) δ 0.97 (d+m, 4H), 1.24 (m, 1H),1.50-1.76 (m, 5H), 2.12 (br t, 1H), 2.28 (s, 3H), 2.36 (s, 3H), 2.49 (brt, 1H), 2.71-2.85 (m, 3H), 3.32 (m, 1H), 3.68 (s, 2H), 3.85 (m, 2H),4.08 (m, 2H), 4.12 (m) and 4.39 (m) (total 1H), 6.01 (s) and 6.10 (s)(total 1H), 6.95 (m) and 7.01 (m) (total 1H), 7.02 (s) and 7.06 (s)(total 1H), 7.13 (s, 1H), 7.22 (m) and 7.37 (m) (total 1H), 8.07 (br s)and 8.55 (br s) (total 1H); ES-MS m/z 578 (M+H).

Example 12

Compound 122,6-Dichloro-4-methyl-N—((R)-3-{4-[(2-morpholin-4-yl-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-nicotinamide

A solution of methyl N-morpholinoacetate (0.85 g, 5.3 mmol) in 1:1 5NNaOH/THF (10 ml) was stirred at 50° C. for 1 h then neutralized to pH 3with 6N HCl and concentrated. The yellowish solid was diluted with 1:1MeOH/CH₂Cl₂ (25 ml), filtered to remove inorganic salts, andconcentrated. The dilution, filtration and concentration were repeatedto give morpholin-4-yl-acetic acid (695 mg, 90%) as a yellow solid.

COMPOUND 12 was isolated as a white solid (mixture of rotationalisomers). ¹H NMR (CDCl₃) δ 0.96-1.84 (m, 8H), 2.00-2.27 (m, 1H),2.31-2.57 (m, 7H), 2.68-2.99 and 3.29-3.41 (m, 3H), 3.06 and 3.20 (s,2H), 3.48 (s, 2H), 3.65-3.92 (m, 6H), 3.95-4.51 (m, 3H), 6.97-7.01 (m,2H), 7.13 (s, 1H), 7.18-7.21 and 7.32-7.35 (m, 1H), 8.15 and 8.77 (br s,1H); ¹³C NMR (CDCl₃) δ 13.67, 19.59, 29.25, 29.93, 30.95, 31.39, 31.99,39.91, 40.62, 42.57, 44.01, 44.49, 52.00, 52.26, 53.84, 54.15, 55.96,59.96, 60.47, 61.61, 62.46, 67.19, 120.85, 122.28, 124.79, 125.66,126.23, 127.21, 128.02, 140.19, 147.01, 150.23, 151.31, 164.70, 169.26,169.98; ES-MS m/z 582 (M+H).

Example 13

Compound 132,6-Dichloro-4-methyl-N—((R)-3-{4-[(2-pyridin-2-yl-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-nicotinamide

Yellowish solid (mixture of rotational isomers). ¹H NMR (CDCl₃) δ0.91-1.85 (m, 9H), 2.35 and 2.37 (s, 3H), 2.39-3.02 (m, 4H), 3.23-3.46(m, 1H), 3.68-3.81 (m, 3H), 3.97-4.53 (m, 4H), 6.97 and 7.01 (d, 1H,J=4.8 Hz), 7.07-7.25 (m, 4H), 7.28-7.39 (m, 1H), 7.59-7.69 (m, 1H), 8.51(d, 1H, J=4.8 Hz), 8.24 and 8.67 (br s, 1H); ¹³C NMR (CDCl₃) δ 13.40,13.51, 19.28, 29.07, 29.79, 30.70, 30.99, 31.39, 39.56, 40.48, 43.17,43.81, 43.98, 44.73, 51.60, 51.71, 53.56, 55.97, 59.72, 60.08, 120.91,121.69, 121.95, 122.19, 123.76, 124.49, 124.59, 125.30, 126.04, 126.85,127.55, 132.52, 136.63, 136.92, 139.79, 149.32, 149.48, 150.00, 150.93,155.83, 164.44, 169.87, 171.11; ES-MS m/z 574 (M+H).

Example 14

Compound 142,6-Dichloro-4-methyl-N—((R)-3-{4-[(2-pyridin-3-yl-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-nicotinamide

White solid (mixture of rotational isomers). ¹H NMR (CDCl₃) δ 0.91-1.90(m, 9H), 1.98-2.24 (m, 1H), 2.34 and 2.37 (s, 3H), 2.48-2.62 (m, 1H),2.64-2.82 (m, 3H), 3.22-3.43 (m, 1H), 3.56 (s, 2H), 3.72-3.91 (m, 1H),3.95-4.19 (m, 2H), 4.32-4.51 (m, 1H), 6.93-7.13 (m, 3H), 7.21-7.26 (m,1H), 7.38-7.40 (m, 1H), 7.52 and 7.65 (d, 1H, J=7.8 Hz), 8.02 and 8.29(s, 1H), 8.48-8.52 (m, 1H), 8.73 (br s, 1H); ¹³C NMR (CDCl₃) δ 13.47,19.25, 29.53, 30.29, 30.61, 31.18, 31.81, 38.03, 38.37, 29.61, 40.00,40.53, 43.01, 43.51, 44.00, 51.72, 52.07, 56.65, 59.45, 60.22, 120.92,121.90, 123.43, 123.67, 124.48, 125.50, 125.83, 127.29, 127.59, 130.86,132.66, 136.64, 136.86, 139.56, 146.70, 148.30, 148.52, 149.95, 150.12,151.08, 164.20, 170.75; ES-MS m/z 574 (M+H).

Example 15

Compound 152,6-Dichloro-4-methyl-N—((R)-3-{4-[(2-pyridin-4-yl-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-nicotinamide

Yellowish solid (mixture of rotational isomers). ¹H NMR (CDCl₃) δ0.93-1.78 (m, 9H), 2.07-2.26 (m, 1H), 2.34 and 2.38 (s, 3H), 2.50-2.69(m, 1H), 2.70-2.96 (m, 3H), 3.24-3.54 (m, 1H), 3.56 (s, 2H), 3.71-3.92(m, 1H), 3.97-4.18 (m, 2H), 4.33-4.52 (m, 1H), 6.95-7.21 (m, 6H),7.37-7.39 (m, 1H), 8.50-8.56 (m, 1H), 7.95 and 8.70 (br s, 1H); ¹³C NMR(CDCl₃) δ 13.46, 19.31, 29.35, 30.09, 30.66, 31.22, 31.74, 39.91, 40.39,40.85, 43.09, 43.57, 44.03, 51.78, 56.73, 59.53, 60.29, 120.98, 122.06,124.18, 124.40, 124.50, 125.57, 125.84, 127.35, 127.65, 132.64, 139.47,144.08, 146.72, 149.96, 150.21, 151.11, 164.28, 170.24; ES-MS m/z 574(M+H).

Example 16

Compound 162,6-Dichloro-N—((R)-3-{4-[(3-methoxy-propionyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

¹H NMR (CDCl₃) mixture of rotamers (˜3:1) δ 0.90-0.96 (m, 4H), 1.08-2.12(m, 7H), 2.03-2.19 (m, 1H), 2.34-2.82 (m, 8H), 3.28-3.35 (m, 4H),3.61-3.85 (m, 3H), 4.02-4.48 (m, 2H), 6.93-7.01 (m, 2H), 7.12-7.18 (m,1H), 7.30-7.32 (m, 1H), 8.25 (br s) and 8.80 (br s) (total 1H); ES-MSm/z 563 (M+Na).

Example 17

Compound 172,6-Dichloro-4-methyl-N—((R)-3-{4-[(2-tetrazol-2-yl-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-nicotinamide

White foam (mixture of rotational isomers). ¹H NMR (CDCl₃) δ 0.97-0.99(m, 3H), 1.05-1.18 (m, 1H), 1.20-1.39 (m, 1H), 1.59 (s, 3H), 1.61-1.84(br m, 4H), 2.14-2.21 (m, 1H), 2.36 (s, 3H), 2.51-2.67 (m 1H), 2.73-2.93(m, 3H), 3.27-3.42 (m, 1H), 3.77-3.89 (m, 1H) 4.20 (s, 2H), 4.25-4.46(m, 1H), 5.12 (s, 2H), 6.98-7.04 (m, 1H), 7.13 (br s, 2H), 7.45 (br s,1H), 8.52 (br s, 1H), 8.78 (s, 1H); ES-MS m/z 565 (M+H).

Example 18

Compound 182,6-Dichloro-4-methyl-N—[(R)-3-(4-{[2-(2-oxo-pyrrolidin-1-yl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-nicotinamide

N-Acetylglycine (0.031 ml, 0.22 mmol) was dissolved in 1:1 10N NaOH/THF(2 ml) and was stirred at 50° C. for 1 h. The mixture was neutralized topH 4 with 6N HCl, then concentrated. The yellowish solid was dilutedwith 1:1 MeOH/CH₂Cl₂ (25 ml), filtered to remove inorganic salts, andconcentrated. The solid obtained was diluted again with 1:1 MeOH/CH₂Cl₂and concentrated to give (2-oxo-pyrrolidin-1-yl)-acetic acid as a whitesolid. The crude product was used in the next reaction withoutpurification.

COMPOUND 18 was isolated as a white foam (mixture of rotamers). ¹H NMR(CDCl₃) δ 0.97-0.99 (d, 3H, J=6 Hz), 1.05-1.19 (m, 1H), 1.20-1.32 (m,1H), 1.48-1.72 (m, 3H), 1.73-1.87 (m, 1H), 1.93-2.23 (m, 4H), 2.34 (s,3H), 2.47-2.54 (m, 1H), 2.69-2.93 (m, 3H), 3.24-3.58 (m, 3H), 3.68-3.83(m, 1H), 3.97 (s, 2H), 3.99-4.20 (m, 2H), 4.29-4.43 (m, 1H), 7.01-7.02(d, 1H, J=3 Hz), 7.10 (s, 1H), 7.19 (s, 1H), 7.34-7.35 (d, 1H, J=3 Hz),8.21 (br s, 1H), 8.63 (br s, 1H); ¹³C NMR (CDCl₃) δ 13.38, 18.14, 19.30,27.36, 29.27, 29.98, 30.49, 30.70, 30.91, 31.58, 39.84, 40.57, 42.28,43.58, 43.81, 44.87, 48.18, 51.73, 52.22, 55.26, 59.68, 60.12, 120.10,121.03, 122.04, 124.62, 125.63, 125.92, 126.63, 127.19, 127.58, 131.22,132.62, 139.05, 146.73, 150.01, 151.09, 164.35, 168.21, 175.99; ES-MSm/z 580 (M+H).

Example 19

Compound 19N—((R)-3-{4-[(2-Benzoylamino-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,6-dichloro-4-methyl-nicotinamide

White solid (mixture of rotational isomers). ¹H NMR (CDCl₃) δ 0.99-1.01(m, 3H), 1.18-1.27 (m, 1H), 1.32-1.91 (m, 5H), 2.12-2.26 (m, 1H), 2.35and 2.38 (s, 3H), 2.49-2.66 (m, 1H), 2.73-3.00 (m, 3H), 3.26-3.87 (m,3H), 4.10-4.30 (m, 4H), 6.96-7.00 (m, 1H), 7.05-7.08 (m, 1H), 7.12 (d,1H, J=4.5 Hz), 7.21-7.25 (m, 1H), 7.35-7.45 (m, 3H), 7.80-7.84 (m, 2H),8.12-8.15 (m, 1H), 8.52-8.60 (m, 1H); ¹³C NMR (CDCl₃) δ 13.42, 19.32,29.30, 29.83, 30.81, 31.10, 39.74, 40.86, 42.22, 42.41, 42.65, 43.65,51.48, 51.80, 53.23, 54.86, 59.78, 60.19, 121.17, 122.08, 124.57,124.67, 125.89, 126.38, 127.20, 127.36, 127.44, 128.69, 128.86, 131.77,131.90, 132.81, 138.33, 139.14, 151.07, 164.41; ES-MS m/z 616(M+H).

Example 20

Compound 202,6-Dichloro-N—((R)-3-{4-[(2-imidazol-1-yl-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

Yellowish solid (mixture of rotational isomers). ¹H NMR (CDCl₃) δ 0.98(d, 3H, J=6 Hz), 1.01-1.15 and 1.23-1.34 (m, 1H), 1.44-1.82 (m, 5H),2.07-2.23 (m, 1H), 2.35 (s, 3H), 2.48-2.59 (m, 1H), 2.68-2.93 (m, 3H),3.26-3.40 (m, 1H), 3.72-3.88 (m, 1H), 3.82 (s, 2H), 4.27-4.46 (m, 1H),4.58 (s, 2H), 6.83-6.84 (m, 1H), 7.02-7.11 (m, 4H), 7.31-7.43 (m, 2H),8.66 (br s, 1H); ¹³C NMR (CDCl₃) δ 13.52, 19.31, 29.37, 30.04, 30.75,39.82, 41.10, 42.55, 43.61, 48.35, 51.57, 52.65, 53.64, 60.13, 120.23,121.13, 122.61, 124.58, 125.67, 127.94, 129.28, 132.69, 138.07, 146.64,149.85, 151.20, 164.26, 167.03; ES-MS m/z 563 (M+H).

Example 21

Compound 212,6-Dichloro-4-methyl-N—((R)-3-{4-[thiophen-3-ylmethyl-(2-ureido-acetyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide

¹H NMR (CDCl₃) (mixture of rotamers) δ 0.99 (m, 3H), 1.08-1.33 (m, 2H),1.41-1.72 (m, 5H), 2.13 (m, 1H), 2.37 (s+s, 3H), 2.51 (br t, 1H),2.74-2.83 (m, 3H), 3.32 (m, 1H), 3.48 (m) and 4.25 (m) (total 1H), 3.80(m, 1H), 3.96 (m, 1H), 4.07-4.25 (m, 3H), 5.73 (br s) and 6.09 (br s)(total 1H), 6.93 (m, 1H), 6.99 (s) and 7.04 (s) (total 1H), 7.15 (s,1H), 7.23 (m) and 7.33 (m) (total 1H), 8.17 (br s) and 8.56 (br s)(total 1H); ES-MS m/z 555 (M+H).

Example 22

Compound 222,6-Dichloro-N—((R)-3-{4-[(2-dimethylamino-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.96-0.98 (m, 4H), 1.15-1.22 (m, 2H),1.48-1.49 (m, 1H), 1.70-1.75 (m, 1H), 2.11-2.27 (m, 8H), 2.35-2.39 (m,4H), 2.53-2.57 (m, 1H), 2.68-2.82 (m, 3H), 2.98-3.11 (m, 2H), 3.29-3.34(m, 1H), 3.80-3.86 (m, 1H), 4.13-4.37 (m, 2H), 6.91-7.03 (m, 2H), 7.12(m, 1H), 7.32-7.34 (m, 1H), 8.72 (br S, 1H); ES-MS m/z 562 (M+Na).

Example 23

Compound 232,6-Dichloro-N—((R)-3-{4-[(2-methanesulfonyl-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.96-0.99 (m, 3H), 1.01-1.45 (m, 2H),1.60-1.77 (m, 5H), 2.14 (m, 1H), 2.35-2.37 (m, 3H), 2.52-2.53 (m, 1H),2.72-2.85 (m, 3H), 3.11-3.14 (m, 3H), 3.30 (m, 1H), 3.76-3.81 (m, 1H),3.90 (s, 1H), 4.12 (m, 1H), 4.22-4.31 (m, 2H), 7.00-7.04 (m, 2H), 7.05(s, 1H), 7.38 (m, 1H), 8.38 (br s, 1H); ES-MS m/z 597 (M+Na).

Example 24

Compound 242,6-Dichloro-4-methyl-N—[(R)-3-(4-{[2-(2-oxo-oxazolidin-3-yl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-nicotinamide

To a solution of 3-(2-hydroxy-ethyl)-oxazolidin-2-one (0.575 g, 4.38mmol) in acetone (40 ml) was added 15% aqueous sodium bicarbonate (12ml) to give a white slurry, which was then cooled to 0° C. (JOC 2003,68, 4999-5001). Sodium bromide (0.090 g, 0.88 mmol) and TEMPO (0.014 g,0.09 mmol) were added and the resulting mixture was stirred for 10minutes followed by the addition of trichloroisocyanuric acid (2.03 g,8.76 mmol) in four equal portions added every five minutes. The paleyellow slurry was warmed to 25° C. and stirred for an additional 12hours to yield a yellow solution. Iso-propanol (3 ml) was added and themixture was stirred for 45 minutes to give a white slurry, which wasfiltered through a Celite® cake. The filtrate was concentrated in vacuo,quenched with saturated aqueous sodium bicarbonate and extracted withethyl acetate (30 ml). The aqueous phase was acidified with 4N HCl untilpH ˜2 and then put on for continuous extraction with methylene chloride(˜100 ml) for 16 hours. The organic extract was dried over sodiumsulfate, filtered and concentrated in vacuo to yield(2-oxo-oxazolidin-3-yl)-acetic acid (0.445 g, 70%) as a pale yellowsolid.

COMPOUND 24 was isolated as a white foam. ¹H NMR (CDCl₃) (mixture ofrotamers) δ 0.97 (d+m, 4H), 1.22 (m, 1H), 1.51-1.75 (m, 4H), 2.10 (br t,1H), 2.36 (s, 3H), 2.49 (br t, 1H), 2.72-2.82 (m, 3H), 3.32 (m, 1H),3.64-3.84 (m, 3H), 3.94 (s, 2H), 4.05-4.11 (s+m, 3H), 4.35 (m, 3H),6.95-7.09 (m, 2H), 7.15 (s, 1H), 7.21 (m) and 7.36 (m) (total 1H), 8.12(br s) and 8.64 (br s) (total 1H); ES-MS m/z 582 (M+H).

Example 25

Compound 25N—{(R)-3-[4-(Acryloyl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-2,6-dichloro-4-methyl-nicotinamide

¹H NMR (CDCl₃) (mixture of rotamers) δ 0.98 (d+m, 4H), 1.23 (m, 1H),1.50-1.76 (m, 4H), 2.16 (br t, 1H), 2.37 (s, 3H), 2.54 (br t, 1H),2.70-2.81 (m, 3H), 3.27 (m, 1H), 3.81 (m, 1H), 4.08 (m, 2H), 4.45 (m,1H), 5.63 (m, 1H), 6.37 (m, 2H), 6.99 (s+d, 2H), 7.14 (s, 1H), 7.19 (m)and 7.33 (m) (total 1H), 8.09 (br s) and 8.81 (br s) (total 1H); ES-MSm/z 509 (M+H).

Example 26

Compound 26N—((R)-3-{4-[(3-Acetylamino-propionyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,6-dichloro-4-methyl-nicotinamide

Mixture of rotational isomers (˜2:1). ¹H NMR (CDCl₃) δ 0.81-1.37 (m,5H), 1.47-1.85 (m, 4H), 1.94 (s, 3H), 2.01-2.20 (m, 1H), 2.35-2.58 (m,5H), 2.71-2.84 (m, 3H), 3.25-3.31 (m, 1H), 3.42-3.50 (m, 4H), 3.74-3.84(m, 1H), 4.01-4.39 (m, 2H), 6.37-6.41 (m, 1H), 6.93 (d, 1H, J=5.1 Hz),6.96-6.99 (m, 1H), 7.11-7.16 (m, 1H), 7.23 (dd, J=4.8, 3 Hz) and 7.35(dd, J=4.8, 3 Hz) (total 1H), 8.21 (br s) and 8.64 (br s) (total 1H);¹³C NMR (CDCl₃) δ 13.77, 19.56, 23.77, 30.03, 30.89, 31.30, 32.01,33.56, 33.89, 35.51, 40.13, 40.46, 40.66, 43.25, 43.85, 44.09, 51.99,52.14, 52.59, 55.98, 60.04, 60.57, 121.05, 121.76, 124.80, 124.87,125.92, 126.10, 127.33, 127.60, 132.75, 132.95, 139.49, 140.17, 147.01,150.24, 150.57, 151.35, 164.48, 164.59, 170.27, 170.57, 171.76, 172.96;ES-MS m/z 590 (M+Na). Anal. Calcd. for C₂₆H₃₅N₅O₃SCl₂·0.8CH₂Cl₂·0.4H₂O:C, 50.01; H, 5.86; N, 10.88. Found: C, 49.79; H, 5.82; N, 10.88.

Example 27

Compound 272,6-Dichloro-4-methyl-N—((R)-3-{4-[thiophen-3-ylmethyl-(2-[1,2,4]-triazol-1-yl-acetyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide

¹H NMR (CDCl₃) δ 0.96 (d, 3H, J=6 Hz), 0.96-1.02 (m, 1H), 1.04-1.13 (m,1H), 1.59-1.86 (m, 3H), 2.07-2.18 (m, 1H), 2.36 (s, 3H), 2.37-2.42 (m,1H), 2.48-2.57 (m, 1H), 2.71-2.86 (m, 4H), 3.26-3.41 (m, 1H), 3.74-3.84(m, 1H), 4.16 (s, 2H), 4.27-4.35 (m, 1H), 4.86 (s, 2H), 7.04-7.08 (m,1H), 7.13 (s, 1H), 7.42 (br s, 1H), 7.93 (s, 1H), 8.15 (s, 1H), 8.59 (brs, 1H); ES-MS m/z 586 (M+Na).

Example 28

Compound 282,6-Dichloro-4-methyl-N—((R)-3-{4-[(2-pyrrolidin-1-yl-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-nicotinamide

¹H NMR (CDCl₃) δ 0.87-1.02 (m, 4H), 1.08-1.13 (m, 1H), 1.59-1.67 (m,2H), 1.76-1.84 (m, 4H), 2.11-2.18 (m, 1H), 2.35 (s, 3H), 2.49-2.58 (m,4H), 2.76-2.89 (m, 2H), 3.18 (br s, 2H), 3.27-3.41 (m, 3H), 3.47-3.53(m, 1H), 3.76-3.87 (m, 2H), 4.17 (d, 1H, J=12 Hz), 4.28-4.42 (m, 1H),6.95-7.02 (m, 3H), 7.12 (s, 1H), 7.30-7.34 (m, 1H), 8.24 and 8.79 (br s,1H); ES-MS m/z 566 (M+H).

Example 29

Compound 292,6-Dichloro-4-methyl-N—((R)-3-{4-[(3-methyl-but-2-enoyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-nicotinamide

¹H NMR (CDCl₃) (mixture of rotamers) δ 0.97 (d+m, 4H), 1.13 (m, 1H),1.49-1.60 (m, 4H), 1.75 (s) and 1.86 (s) (total 3H), 1.91 (s) and 1.97(s) (total 3H), 2.17 (br t, 1H), 2.37 (s, 3H), 2.56 (br t, 1H),2.68-2.80 (m, 3H), 3.30 (m, 1H), 3.81 (m, 1H), 4.03 (m, 2H), 4.39 (m,1H), 5.73 (s) and 5.79 (s) (total 1H), 6.98 (m, 2H), 7.15 (s, 1H), 7.20(m) and 7.31 (m) (total 1H), 8.21 (br s) and 8.85 (br s) (total 1H);ES-MS m/z 537 (M+H).

Example 30

Compound 306-Chloro-2,4-dimethyl-N—[(R)-3-(4-{[2-(2-oxo-pyrrolidin-1-yl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-nicotinamide

¹H NMR (CDCl₃) mixture of rotational isomers δ 0.79-086 (m, 1H), 0.95(d, 3H, J=6 Hz), 0.98-1.09 (m, 1H), 1.48-1.68 (m, 2H), 1.72-1.78 (m,1H), 1.98-2.16 (m, 4H), 2.29 (s, 3H), 2.33-2.41 (m, 2H), 2.47-2.54 (m,4H), 2.67-2.86 (m, 3H), 3.22-3.29 (m, 1H), 3.42 (t, 2H, J=6 Hz),3.47-3.53 (m, 1H), 3.73-3.83 (m, 1H), 3.89-3.99 (m, 2H), 4.12 (br s,1H), 4.25-4.41 (m, 1H), 7.00-7.11 (m, 2H), 7.11 (s, 1H), 7.32-7.37 (m,1H), 7.98 and 8.65 (br s, 1H); ES-MS m/z 582 (M+Na).

Example 31

Compound 316-Chloro-2,4-dimethyl-N—((R)-3-{4-[(2-tetrazol-2-yl-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-nicotinamide

¹H NMR (CDCl₃) δ 0.90-0.95 (m, 1H), 0.97 (d, 3H, J=6 Hz), 1.06-1.16 (m,1H), 1.51-1.57 (m, 1H), 1.63-1.81 (m, 3H), 2.05-2.16 (m, 1H), 2.30 (s,3H), 2.50 (s, 3H), 2.50-2.57 (m, 1H), 2.69-2.84 (m, 3H), 3.23-3.27 (m,1H), 3.78-3.91 (m, 1H), 4.07 (d, 2H, J=9 Hz), 4.29-4.42 (m, 1H), 5.12(s, 2H), 7.02 (s, 1H), 7.09 (d, 1H, J=3 Hz), 7.16 (s, 1H), 7.42-7.47 (m,1H), 8.55 (br s, 1H), 8.75 (s, 1H); ES-MS m/z 567 (M+Na).

Example 32

Compound 326-Chloro-N—((R)-3-{4-[(2-cyano-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) mixture of rotamers (˜4:1) δ 0.90-1.15 (m, 5H), 1.53-1.73(m, 4H), 2.15 (t, 1H, J=12 Hz), 2.28-2.31 (m, 3H), 2.47-2.52 (m, 4H),2.68-2.83 (m, 3H), 3.25-3.53 (m, 3H), 3.85-4.43 (m, 4H), 6.99-7.05 (m,3H), 7.25 (br s) and 7.40 (dd, J=7, 4 Hz) (total 1H), 7.71 (br s) and8.54 (br s) (total 1H); ¹³C NMR (CDCl₃) mixture of rotamers (˜4:1) δ13.5, 18.7, 22.1, 25.7, 29.4, 30.3, 30.6, 40.1, 42.8, 43.1, 51.6, 52.5,60.6, 113.8, 121.1, 122.1, 122.6, 125.5, 127.9, 137.9, 147.7, 150.1,155.4, 162.6, 166.9; ES-MS m/z 524 (M+Na). Anal Calcd. forC₂₅H₃₂N₅O₂SCl·0.2H₂O: C, 59.38; H, 6.46; N, 13.85. Found: C, 59.36; H,6.39; N, 13.73.

Example 33

Compound 336-Chloro-2,4-dimethyl-N—[(R)-3-(4-{[2-(2-oxo-oxazolidin-3-yl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-nicotinamide

¹H NMR (CDCl₃) (mixture of rotamers) δ 0.98 (d+m, 5H), 1.51-1.75 (m,4H), 2.12 (br t, 1H), 2.30 (s, 3H), 2.49 (s+br t, 4H), 2.70-2.79 (m,3H), 3.29 (m, 1H), 3.66-3.83 (m, 3H), 3.93 (s+m, 4H), 4.36 (m, 3H),6.95-7.10 (m, 3H), 7.36 (s, 1H), 7.93 (br s) and 8.64 (br s) (total 1H).ES-MS m/z 562 [M+H]⁺. Anal Calcd. for C₂₇H₃₆N₅O₄SCl: C, 55.80; H, 6.28;N, 11.92. Found: C, 55.64; H, 6.39; N, 11.83.

Example 34

Compound 346-Chloro-N—((R)-3-{4-[(2-methoxyimino-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) mixture of rotamers (˜2:1) δ 0.91-1.76 (m, 9H), 2.02-2.23(m, 1H), 2.30-2.33 (m, 3H), 2.41-2.56 (m, 4H), 2.66-2.84 (m, 3H),3.25-3.41 (m, 1H), 3.78-4.48 (m, 7H), 7.01-7.05 (m, 3H), 7.24 (br s) and7.33 (dd, J=6, 6 Hz) (total 1H), 7.60 (s) and 7.71 (s) (total 1H), 7.99(br s) and 8.61 (br s) (total 1H); ES-MS m/z 542 (M+Na).

Example 35

Compound 356-Chloro-N—((R)-3-{4-[(1-cyano-cyclopropanecarbonyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.82-0.99 (m, 1H), 1.00 (d, 3H, J=7 Hz), 1.15-1.58 (m,7H), 1.72-1.77 (m, 3H), 2.20 (t, 1H, J=12 Hz), 1.77 (s, 3H), 2.52-2.56(m, 4H), 2.75-2.88 (m, 3H), 3.26-3.37 (m, 1H), 3.79-3.84 (m, 1H),3.98-4.28 (m, 3H), 6.95 (d, 1H, J=6 Hz), 6.97 (s, 1H), 7.05 (br s, 1H),8.06 (br s, 1H); ES-MS m/z 550 (M+Na).

Example 36

Compound 366-Chloro-2,4-dimethyl-N—[(R)-3-(4-{[2-(2-oxo-imidazolidin-1-yl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-nicotinamide

To a solution of 1-(2-hydroxy-ethyl)-imidazolidin-2-one (1.00 g, 7.68mmol) in acetone (70 ml) was added 15% aqueous sodium bicarbonate (21ml) to give a white slurry, which was then cooled to 0° C. (JOC 2003,68, 4999-5001). Sodium bromide (0.16 g, 1.54 mmol) and TEMPO (0.024 g,0.15 mmol) were added and the resulting mixture was stirred for 10minutes followed by the addition of trichloroisocyanuric acid (3.57 g,15.4 mmol) in four equal portions added every five minutes. The paleyellow slurry was warmed to 25° C. and stirred for an additional 12hours to yield a yellow solution. Iso-propanol (9 ml) was added and themixture was stirred for 45 minutes to give a white slurry, which wasfiltered through a Celite® cake. The filtrate was concentrated in vacuo,quenched with saturated aqueous sodium bicarbonate and extracted withethyl acetate (50 ml). The aqueous phase was acidified with 4N HCl untilpH 2 and then put on for continuous extraction with 5% methanol inmethylene chloride (˜120 ml) for 16 hours. The organic extract was driedover sodium sulfate, filtered and concentrated in vacuo to yield(2-oxo-imidazolidin-1-yl)-acetic acid (0.530 g, 48%) as a white solid.

COMPOUND 36 was isolated as a white foam. ¹H NMR (CDCl₃) (mixture ofrotamers) δ 0.98 (d+m, 5H), 1.53-1.70 (m, 4H), 2.11 (br t, 1H), 2.30(s+br t, 4H), 2.37 (s+m, 4H), 2.66 (m, 1H), 2.79 (m, 2H), 3.24 (m, 2H),3.44-3.61 (m, 3H), 3.83-3.98 (m, 4H), 4.36 (m, 2H), 6.97-7.10 (m, 3H),7.21 (m) and 7.35 (m) (total 1H), 8.04 (br s) and 8.69 (br s) (total1H); ES-MS m/z 561 (M+H).

Example 37

Compound 376-Chloro-N—((R)-3-{4-[(2-cyclopropyl-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) mixture of rotational isomers: δ 0.08-0.12 (m, 2H), 0.49(d, 2H, J=6 Hz), 0.54-0.63 (m, 1H), 0.69-0.81 (m, 1H), 0.99 (d, 3H, J=6Hz), 0.99-1.05 (m, 1H), 1.52-1.64 (m, 3H), 1.74-1.82 (m, 2H), 2.16-2.22(m, 3H), 2.29-2.32 (m, 3H), 2.50-2.53 (m, 3H), 2.59-2.82 (m, 3H),3.21-3.28 (m, 1H), 3.76-3.99 (m, 3H), 4.43-4.55 (m, 1H), 6.94-7.02 (m,3H), 7.29-7.35 (m, 1H), 8.80 (br s, 1H); ES-MS m/z 539 (M+Na).

Examples 38 to 49 were prepared following the scheme below whereinR¹COOH and R²COOH are defined in the table.

TABLE 2

Ex- ample R¹COOH R²COOH 38* (tetrahydro-pyran-4-6-chloro-2,4-dimethyl-nicotinic acid yl)-acetic acid 39 methoxyaceticacid 6-chloro-2,4-dimethyl-nicotinic acid 40* methoxyacetic acid5,7-dimethyl-imidazo[1,2-a] pyridine-6-carboxylic acid (see EXAMPLE 280)41 acetic acid 6-fluoro-2,4-dimethyl-nicotinic acid hydrochloride 42methoxyacetic acid 4-cyano-2,6-dimethyl-benzoic acid 43 cyanoacetic acid2,6-chloro-4-methyl-nicotinic acid 44 3,3,3-tri-fluoro-2,6-chloro-4-methyl-nicotinic acid propionic acid 45 cyanoacetic acid6-fluoro-2,4-dimethyl-nicotinic acid hydrochloride 46 cyanoacetic acid6-cyano-2,4-dimethyl-nicotinic acid 47 (2-oxo-oxazolidin-3-6-cyano-2,4-dimethyl-nicotinic acid yl)-acetic acid (see EXAMPLE 24) 48(2-oxo-oxazolidin-3- 6-fluoro-2,4-dimethyl-nicotinic acid yl)-aceticacid (see hydrochloride EXAMPLE 24) 49 (2-oxo-oxazolidin-3-2,6-dichloro-4-methyl-nicotinic yl)-acetic acid (see acid-N-oxide (seeEXAMPLE 191) EXAMPLE 24)

Example 38

Compound 38N-(3-{4-[(Thiophen-3-ylmethyl)-2-(tetrahydro-pyran-4-yl)-acetyl-amino]-piperidin-1-yl}-butyl)-6-chloro-2,4-dimethyl-nicotinamide

White solid. ¹H NMR (CDCl₃) δ 0.73-0.90 (m, 1H), 0.96 (d, 3H, J=6.0 Hz),1.09-3.95 (m, 25H), 2.28 (s, 3H), 2.49 (s, 3H), 4.36-4.56 (m, 1H),6.86-7.14 (m, 3H), 7.31-7.45 (m, 1H), 8.80 (br s, 1H); ¹³C NMR (CDCl₃) δ13.79, 19.16, 22.45, 28.86, 29.89, 30.82, 31.36, 31.71, 32.24, 32.52,33.26, 33.58, 39.97, 40.59, 40.82, 42.66, 43.63, 44.20, 51.60, 52.22,53.82, 56.13, 60.12, 61.04, 68.25, 120.92, 121.65, 122.86, 123.01,125.71, 126.19, 127.12, 127.81, 133.33, 140.31, 148.06, 150.44, 155.81,167.35, 172.65; ES-MS m/z 561 (M+1).

Example 39

Compound 396-Chloro-N—((R)-3-{4-[2-methoxy-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

White solid. ¹H NMR (CD₃OD) δ 1.03 (d, 3H, J=6.6 Hz), 1.55-1.87 (m, 6H),2.06-2.29 (m, 4H), 2.43-2.49 (m, 4H), 2.74-2.87 (m, 3H), 3.06-3.63 (m,7H), 4.07 (s, 1H), 4.26 (s, 1H), 4.33-4.49 (d, 2H, J=8.7 Hz), 7.00 (d,1H, J=4.8 Hz), 7.16-7.21 (m, 2H), 7.29-7.43 (s, 1H); ¹³C NMR (CD₃OD) δ13.84, 19.13, 22.42, 29.70, 30.63, 30.98, 40.36, 40.58, 41.80, 43.68,51.94, 59.55, 60.70, 71.51, 120.94, 122.88, 126.17, 127.23, 133.24,139.74, 148.03, 156.37, 155.69, 167.37, 171.71. Anal. Calcd. forC₂₅H₃₅N₄O₃S·0.12CH₂Cl₂: C, 58.33; H, 6.87; N, 10.83. Found: C, 57.97; H,6.90; N, 10.83.

Example 40

Compound 40 5,7-Dimethyl-imidazo[1,2-a]pyridine-6-carboxylic acid(3-{4-[(2-methoxy-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide

¹H NMR (CDCl₃) mixture of rotational isomers: δ 0.89-1.21 (m, 1H), 0.99(d, 3H, J=6 Hz), 1.49-1.92 (m, 4H), 2.06-2.22 (m, 1H), 2.37 (s, 3H),2.58 (s, 3H), 2.68-2.86 (m, 4H), 3.31 (s, 2H), 3.34-3.51 (m, 6H), 3.79(s, 2H), 3.82-3.96 (m, 1H), 4.01-4.13 (m, 1H), 4.31-4.52 (m, 1H),6.72-6.85 (m, 2H), 7.32 (s, 1H), 7.69 (s, 1H), 8.52 (br s, 1H); ES-MSm/z 512 (M+H).

Example 41

Compound 41N—{(R)-3-[4-(Acetyl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-6-fluoro-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) mixture of rotational isomers δ 0.86 (m, 1H),0.98 (m+d, 4H), 1.52-1.61 (m, 4H), 1.73 (m, 1H), 1.97 (s, 3H), 2.12 (brt, 1H), 2.32 and 2.36 (s and s, total 3H), 2.46 and 2.49 (s and s, total3H), 2.65 (m, 1H), 2.77-2.81 (m, 3H), 3.27 (m, 1H), 3.80 (m, 1H), 3.88and 3.95 (d and d, total 2H), 4.45 (m, 1H), 6.53 and 6.57 (s and s,total 1H), 6.97 (m, 1H), 7.18 and 7.34 (m and m, total 1H), 7.76 and8.68 (m and m, total 1H); ES-MS m/z 461 (M+H). Anal. Calcd. forC₂₄H₃₃N₄O₂SF·0.7H₂O: C, 60.92; H, 7.33; N, 11.84. Found: C, 60.89; H,7.04; N, 11.60.

Example 42

Compound 424-Cyano-N—((R)-3-{4-[(2-methoxy-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-benzamide

White solid. ¹H NMR (CDCl₃) δ 0.75-1.04 (m, 4H), 1.25-1.87 (m, 7H),2.05-2.25 (m, 1H), 2.32, 2.36 (s, 3H), 2.50-2.58 (m, 1H), 2.64-2.92 (m,4H), 3.34 (s, 2H), 3.34-3.41 (m, 1H), 3.49 (s, 3H), 3.87 (m, 2H),4.04-4.16 (m, 1H), 4.32-4.53 (m, 1H), 6.92 (d, 1H, J=4.8 Hz), 6.98-7.00(m, 1H), 7.24-7.26 (m, 2H), 7.35-7.39 (m, 1H), 8.45 (br s, 1H); ES-MSm/z 497 (M+H).

Example 43

Compound 432,6-Dichloro-N—((R)-3-{4-[(2-cyano-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.97-0.99 (d, 3H, J=6.6 Hz), 0.99-1.10 (m,1H), 1.25-1.31 (m, 1H), 1.51 (m, 1H), 1.66-1.76 (m, 3H), 2.11-2.19 (t,1H, J=12 Hz), 2.36 (s, 3H), 2.50-2.58 (t, 1H, J=12 Hz), 2.73-2.96 (m,3H), 3.31-3.34 (m, 3H), 3.79-3.86 (m, 1H), 4.05 (s, 2H), 4.29-4.33 (m,1H), 6.98-7.00 (d, 1H, J=5.1 Hz), 7.06 (s, 1H), 7.13-7.15 (m, 1H),7.40-7.42 (m, 1H), 8.58 (br s, 1H); ES-MS m/z 544 (M+Na).

Example 44

Compound 442,6-Dichloro-4-methyl-N—((R)-3-{4-[thiophen-3-ylmethyl-(3,3,3-trifluoro-propionyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide

Yellow foam. ¹H NMR (CDCl₃) δ 0.96-1.00 (m, 4H), 1.21 (m, 1H), 1.50 (m,1H), 1.62-1.76 (m, 3H), 2.10-2.14 (m, 1H), 2.36 (s, 3H), 2.53 (m, 1H),2.71-2.84 (m, 3H), 3.03-3.13 (m, 2H), 3.26-3.29 (m, 1H), 3.79-3.86 (m,1H), 4.04 (s, 2H), 4.38-4.46 (m, 1H), 7.00-7.04 (m, 2H), 7.14 (s, 1H),7.38-7.39 (m, 1H), 8.66 (br s, 1H); ES-MS m/z 587 (M+Na).

Example 45

Compound 45N—((R)-3-{4-[(2-Cyano-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-6-fluoro-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) (mixture of rotamers) δ 0.99 (d+m, 4H), 1.14 (m, 1H),1.58 (m, 1H), 1.69 (m, 3H), 2.17 (br t, 1H), 2.32 (s) and 2.36 (s)(total 3H), 2.46 (s) and 2.50 (s) (total 3H), 2.54 (brt, 1H), 2.70-2.82(m, 3H), 3.31 (s+m, 3H), 3.76 (m, 1H), 3.92 (s, 2H), 4.43 (m, 1H), 6.50(s) and 6.58 (s) (total 1H), 6.96 (d, J=6.0 Hz, 1H), 7.03 (s, 1H), 7.41(m, 1H), 8.46 (br s, 1H); ES-MS m/z 486 (M+H). Anal Calcd. forC₂₅H₃₂N₅O₂SF: C, 61.15; H, 6.59; N, 14.26; F, 3.87; S, 6.53. Found: C,61.15; H, 6.59; N, 14.37; F, 3.95; S, 6.47.

Example 46

Compound 466-Cyano-N—((R)-3-{4-[(2-cyano-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) (mixture of rotamers) δ 0.99 (d+m, 4H), 1.22 (m, 1H),1.56 (m, 1H), 1.67 (m, 3H), 2.16 (br t, 1H), 2.35 (s) and 2.37 (s)(total 3H), 2.55 (s+br t, 4H), 2.71-2.88 (m, 3H), 3.34 (s+m, 3H), 3.78(m, 1H), 4.00 (s, 2H), 4.33 (m, 1H), 6.97 (d, 1H, J=6.0 Hz), 7.06 (s,1H), 7.35 (s, 1H), 7.43 (m, 1H), 8.39 (br s, 1H); ES-MS m/z 493 (M+H).

Example 47

Compound 476-Cyano-2,4-dimethyl-N—[(R)-3-(4-{[2-(2-oxo-oxazolidin-3-yl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-nicotinamide

¹H NMR (CDCl₃) (mixture of rotamers) δ 0.94 (d+m, 4H), 1.10 (m, 1H),1.61-1.76 (m, 4H), 2.13 (br t, 1H), 2.36 (s, 3H), 2.49 (br t, 1H), 2.56(s, 3H), 2.69 (m, 1H), 2.81 (m, 1H), 3.34 (m, 1H), 3.66-3.79 (m, 3H),3.91-3.98 (s+s+m, 4H), 4.36 (m, 3H), 7.02 (m, 1H), 7.10 (m, 1H), 7.35(s, 1H), 7.39 (m, 1H), 8.49 (br s, 1H); ES-MS m/z 553 (M+H).

Example 48

Compound 486-Fluoro-2,4-dimethyl-N—[(R)-3-(4-{[2-(2-oxo-oxazolidin-3-yl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-nicotinamide

¹H NMR (CDCl₃) (mixture of rotamers) δ 0.98 (d+m, 4H), 1.12 (m, 1H),1.55-1.77 (m, 4H), 2.14 (br t, 1H), 2.33 (s, 3H), 2.53 (s, 1H), 2.57 (brt, 3H), 2.72 (m, 1H), 2.81 (m, 1H), 3.30 (m, 1H), 3.63-3.79 (m, 3H),3.90-3.98 (s+s+m, 4H), 4.35 (m, 3H), 6.56 (s, 1H), 6.96 (m, 1H), 7.06(s, 1H), 7.22 (m) and 7.36 (m) (total 1H), 7.72 (br s) and 8.49 (br s)(total 1H); ES-MS m/z 546 (M+H).

Example 49

Compound 492,6-Dichloro-4-methyl-N—[(R)-3-(4-{[2-(2-oxo-oxazolidin-3-yl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-nicotinamide-N-oxide

¹H NMR (CDCl₃) (mixture of rotamers) δ 0.97 (m, 1H), 1.08 (d+m, 4H),1.66-1.75 (m, 4H), 1.95 (br t, 1H), 2.34 (s+br t, 4H), 2.60 (m, 1H),2.85 (m, 1H), 2.97 (m, 2H), 3.46 (m, 1H), 3.66-3.73 (m, 3H), 3.97 (s,2H), 4.11 (s, 1H), 4.35 (m, 3H), 6.98 (d, 1H, J=3.0 Hz), 7.10 (s, 1H),7.26 (m) and 7.34 (m) (total 1H), 8.19 (br s) and 8.56 (br s) (total1H); ES-MS m/Z 598 (M+H).

Example 50

Compound 50 4,6-Dimethyl-pyrimidine-5-carboxylic acid(3-{4-[(2-cyclohexyl-2-phenyl-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide

To a solution of 2-phenylcyclohexylacetic acid (200 mg, 0.92 mmol) inbenzene (10 ml) at rt was added thionyl chloride (0.67 ml, 9 mmol) andthe resultant mixture was heated at reflux for 2 h. The mixture wascooled down, concentrated to remove all volatiles and the residue wastaken into benzene (5 ml). {4,6-Dimethyl-pyrimidine-5-carboxylic acid(3-{4-[(thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (49 mg,0.122 mmol) and Na₂CO₃ (96 mg, 0.9 mmol) were added and the mixture wasstirred at rt for 15 h. The solution was diluted with CH₂Cl₂ (15 ml) andwashed with brine (15 ml), dried (Na₂SO₄), filtered and concentratedunder reduced pressure. Purification of the residue by columnchromatography on silica gel (1:9, MeOH/CH₂Cl₂) afforded COMPOUND 50 asa white solid (44 mg, 60%). ¹H NMR (CDCl₃) δ 0.49-2.25 (m, 22H),2.30-2.80 (m, 10H), 3.00-4.5 (m, 5H), 7.75-7.30 (m, 9H), 8.00-8.95 (m,1H); ¹³C NMR (CDCl₃) δ 14.05, 22.62, 26.87, 27.09, 27.26, 30.35, 31.24,31.32, 31.56, 31.92, 33.43, 40.46, 42.77, 42.84, 43.06, 44.11, 44.24,52.17, 52.34, 52.50, 56.73, 56.78, 60.28, 60.87, 60.77, 121.37, 121.75,121.79, 125.84, 126.71, 127.38, 127.62, 127.89, 129.11, 129.92, 129.31,131.43, 139.14, 139.45, 140.87, 158.11, 158.40, 163.62, 163.66, 167.07,167.16, 174.67; ES-MS m/z 602 (M+H). Anal. Calcd. forC₃₄H₃₇N₅S₂O₂·0.8CH₂Cl₂: C, 64.20; H, 7.31; N, 10.46. Found: C, 64.48; H,7.24; N, 10.29.

Examples 51 to 54 were prepared following the scheme illustrated below.R¹(C═O)Cl is defined in the table.

TABLE 3

Example R¹(C═O)Cl 51 propionyl chloride 52 methyl 4-chloro-4-oxobutyrate53 isobutyrylchloride 54 fluoroacetyl chloride

Example 51

Compound 512,6-Dichloro-4-methyl-N—{(R)-3-[4-(propionyl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.91-1.25 (m, 10H), 1.43 (m, 1H), 1.59 (m,1H), 2.14-2.27 (m, 3H), 2.35-2.39 (m, 3H), 2.53 (m, 1H), 2.69-2.80 (m,3H), 3.25-3.32 (m, 1H), 3.80-3.84 (m, 1H), 3.99-4.00 (m, 2H), 4.38-4.42(m, 1H), 6.91-6.98 (m, 2H), 7.12-7.21 (m, 1H), 7.27-7.34 (m, 1H), 8.83(br s, 1H); ES-MS m/z 533 (M+Na).

Example 52

Compound 52N-(1-{(R)-3-[(2,6-Dichloro-4-methyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-N-thiophen-3-ylmethyl-succinamicacid methyl ester

Mixture of rotational isomers: ¹H NMR (CDCl₃) δ 1.06 (d, 3H, J=6.6 Hz),1.41-1.64 (m, 5H), 1.83-2.00 (m, 1H), 2.25-2.38 (m) and 2.45 (s) (total5H), 2.60-2.70 (m, 4H), 2.84-3.04 (m, 3H), 3.31-3.43 (m, 1H), 3.66-3.73(m, 4H), 4.20-4.28 (m, 2H), 4.45-4.56 (m, 1H), 6.92 (d, J=4.8 Hz) and7.02 (d, J=4.8 Hz) (total 1H), 7.14 (br s, 2H), 7.18 (dd, J=4.8, 3 Hz)and 7.33 (dd, J=4.8, 3 Hz) (total 1H), 8.12 (br s) and 8.55 (br s)(total 1H); ES-MS m/z 569 (M+H).

Example 53

Compound 532,6-Dichloro-N—{(R)-3-[4-(isobutyryl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-4-methyl-nicotinamide

Colorless oil. ¹H NMR (CDCl₃) (mixture of rotamers) δ 1.03 (m, 8H), 1.17(m, 3H), 1.55-1.67 (m, 4H), 2.12 (br t, 1H), 2.36 (s) and 2.38 (s)(total 3H), 2.57 (m+br t, 2H), 2.67-2.80 (m, 4H), 3.30 (m, 1H), 3.83 (m,1H), 4.02 (m, 2H), 3.56 (m) and 4.42 (m) (total 1H), 6.91-6.99 (m, 2H),7.14 (s, 1H), 7.19 (m) and 7.34 (m) (total 1H), 8.19 (br s) and 8.84 (brs) (total 1H); ES-MS m/z 525 (M+H).

Example 54

Compound 546-Chloro-N—((R)-3-{4-[(2-fluoro-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) mixture of rotamers (˜3:1) 60.86-1.10 (m, 5H), 1.47-1.75(m, 4H), 2.04-2.19 (m, 1H), 2.29 (s, 3H), 2.43-2.49 (m, 4H), 2.70-2.82(m, 3H), 3.21-3.30 (m, 1H), 3.80-4.22 (m, 3H), 4.35-5.08 (m, 3H), 6.99(br s, 2H), 7.04 (br s, 1H), 7.24 (br s) and 7.35 (br s) (total 1H),7.82 (br s) and 8.68 (br s) (total 1H); ES-MS m/z 517 (M+Na).

Example 55

Compound 556-Chloro-N—{(R)-3-[(4-(formyl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

Formic acetic anhydride was prepared following a literature procedure(J. Org. Chem., 1988, 53, 2365). The formic acetic anhydride (250 μL)was then added neat to a solution of((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (372 mg, 1.01 mmol) in CH₂Cl₂ (6 ml) and thesolution was allowed to stir at rt overnight. The reaction was dilutedwith CH₂Cl₂ (20 ml) and washed with 1N NaOH (15 ml), isolated and driedover Na₂SO₄, and concentrated. The resultant product was used crude inthe next step.

Following general procedure C: the Boc-protected amine was taken up inCH₂Cl₂ (8 ml) and TFA (1.5 mL) was added. The reaction was allowed tostir for 2 h before solvent was removed. The crude was diluted withCH₂Cl₂ and washed with 1N NaOH before the organic layer was isolated anddried over Na₂SO₄. The crude residue (288 mg, 96% 2 steps) was used asis in the next step.

Following general procedure E: to a solution of the resultant crudeproduct from above in DMF (3.5 ml) was added6-chloro-2,4-dimethylnicotinic acid (120 mg, 0.54 mmol), HOBt (99 mg,0.73 mmol), DIPEA (1 ml, 5.7 mmol) and EDCI (141 mg, 0.73 mmol) and thereaction stirred overnight. Purification of the crude product by flashchromatography on silica gel (MeOH/CH₂Cl₂, 2%) afforded COMPOUND 55 (109mg, 48%) as a white foam (mixture of rotational isomers). ¹H NMR (CDCl₃)δ 0.95-0.98 (m, 3H), 1.01-1.47 (m, 3H), 1.52-1.81 (m, 4H), 2.03-2.17 (m,1H), 2.08 (s, 3H), 2.12-2.24 (m, 1H), 2.32 (s, 3H), 2.67-2.81 (m, 3H),3.16-3.42 (m, 1H), 3.68-4.55 (m, 6H), 6.94-6.99 (m, 1H), 7.06 (s, 1H),7.21-7.24 and 7.31-7.34 (m, 1H), 7.76 and 8.48 (br s, 1H), 8.13 (m, 1H);ES-MS m/z 463 (M+H).

Example 56

Compound 562,6-Dichloro-4-methyl-N—((R)-3-{4-[(2,2,3,3,3-pentafluoro-propionyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-nicotinamide

To a solution of2,6-dichloro-4-methyl-N-(3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(0.085 g, 0.19 mmol) in methylene chloride (4 ml) was addedpentafluoropropionic anhydride (74 μL, 0.38 mmol) and the resultingmixture was stirred at 25° C. for 6 hours. Standard basic workup gavethe crude product as a tan oil. Purification by column chromatography onsilica gel (Et₂O:MeOH:NH₄OH, 94:5:1, v/v/v) afforded COMPOUND 56 (0.045g, 40%) as a white foam. ¹H NMR (CDCl₃) (mixture of rotamers) δ 0.95 (d,J=6.0 Hz) and 0.99 (d, J=6.0 Hz) (total 3H), 1.39 (m, 1H), 1.55 (m, 3H),1.69 (m, 3H), 2.13 (br t, 1H), 2.45 (s, 3H), 2.52 (br t, 1H), 2.82-2.91(m, 3H), 3.36 (m, 1H), 3.73-3.84 (m, 2H), 4.11-4.42 (m, 3H), 6.95 (m,1H), 7.08 (s, 1H), 7.14 (s) and 7.18 (s) (total 1H), 7.24 (m) and, 7.31(m) (total 1H), 7.93 (br s) and 8.19 (br s) (total 1H); ES-MS m/z 601(M+H).

Example 57 was prepared in a similar manner except that difluoroaceticanhydride was used in lieu of pentafluoropropionic anhydride.

Example 57

Compound 576-Chloro-N—((R)-3-{4-[(2,2-difluoro-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) mixture of rotamers (˜1:1) 60.96 (d, J=7 Hz) and 0.99 (d,J=7 Hz) (total 3H), 1.12-1.77 (m, 6H), 2.08 (t, 1H, J=12 Hz), 2.30 (s)and 2.32 (s) (total 3H), 2.50-2.53 (m, 4H), 2.71-2.82 (m, 3H), 3.21-3.29(m, 1H), 3.79-3.83 (m, 1H), 3.98-4.25 (m, 3H), 6.04 (q, J_(F−H)=60 Hz),6.95-7.04 (m, 3H), 7.24 (dd, J=6, 3 Hz) and 7.35 (dd, J=6, 3 Hz) (total1H), 7.95 (br s) and 8.28 (br s) (total 1H); ES-MS m/z 513 (M+H).

Example 58

Compound 58 4,6-Dimethyl-pyrimidine-5-carboxylic acid[3-(4-{[2-(4-chloro-phenylsulfanyl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide

To a solution of 4,6-dimethyl-pyrimidine-5-carboxylic acid(3-{4-[(thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide (85 mg,0.21 mmol) and NaHCO₃ (27 mg, 0.31 mmol) in CH₂Cl₂ (3 ml) was addedchloroacetyl chloride (26.3 mg, 0.23 mmol) and the mixture was stirredat room temperature for 2 h. The mixture was diluted with CH₂Cl₂ (10 ml)and saturated aqueous NaHCO₃ (15 ml). The layers were separated and theaqueous was further extracted with CH₂Cl₂ (2×10 ml). The combinedorganic layers were dried (Na₂SO₄), filtered and concentrated underreduced pressure to give the product as a pure white foam.

To a solution of 4-chlorobenzenethiol (23 mg, 0.16 mmol) and NEt₃ (0.03ml, 0.24 mmol) in CHCl₃ (2 ml) was added the above chloride (50 mg, 0.1mmol). The mixture was stirred at 60° C. for 15 h. The mixture wasdiluted with CH₂Cl₂ (10 ml) and saturated aqueous NaHCO₃ (15 ml). Thelayers were separated and the aqueous was further extracted with CH₂Cl₂(2×10 ml). The combined organic layers were dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The crude material was purified byflash column chromatography on silica gel (9:1, CH₂Cl₂/MeOH) to affordCOMPOUND 58 as a white solid (36 mg, 60%). ¹H NMR (CDCl₃) δ 0.75-1.04(m, 5H), 1.05-1.45 (m, 1H), 2.25-2.80 (m, 12H), 3.25-3.45 (m, 1H), 3.58(s, 2H), 3.76 (s, 6H), 3.80-4.70 (m, 3H), 6.70-7.33 (m, 7H), 7.85 (br s,0.3H), 8.61 (br s, 0.7H), 8.88 (s, 0.7H), 8.92 (s, 0.3H); ¹³C NMR(CDCl₃) δ 13.80, 22.33, 29.78, 30.08, 30.66, 31.01, 31.32, 31.77, 32.12,37.47, 38.00, 39.91, 40.40, 41.02, 43.28, 43.67, 44.14, 51.99, 52.26,57.20, 59.87, 60.61, 121.14, 121.89, 125.80, 126.12, 127.61, 129.50,129.66, 131.27, 132.00, 132.47, 133.57, 139.52, 157.92, 158.10, 163.49,166.67, 166.84, 168.50, 169.10; ES-MS m/z 587 (M+H).

Example 59

Compound 59 4,6-Dimethyl-pyrimidine-5-carboxylic acid[3-(4-{[2-(4-methoxy-phenylsulfanyl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide

To a solution of 4-methoxybenzenethiol (33 mg, 0.23 mmol) and NEt₃ (0.03ml, 0.24 mmol) in CHCl₃ (2 ml) was added4,6-dimethyl-pyrimidine-5-carboxylic acid(3-{4-[(2-chloro-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide(see EXAMPLE 58) (55 mg, 0.11 mmol). The mixture was stirred at 61° C.for 15 h. The mixture was diluted with CH₂Cl₂ (10 ml) and saturatedaqueous NaHCO₃(15 ml). The layers were separated and the aqueous wasfurther extracted with CH₂Cl₂ (2×10 ml). The combined organic layerswere dried (Na₂SO₄), filtered and concentrated under reduced pressure.The crude material was purified by flash column chromatography on silicagel (9:1, CH₂Cl₂/MeOH) to afford COMPOUND 59 as a white solid (42 mg,65%). ¹H NMR (CDCl₃) δ 0.76-2.25 (m, 12H), 2.25-2.80 (m, 12H), 3.25-3.45(m, 1H), 3.58 (s, 2H), 3.76 (s, 6H), 3.80-4.70 (m, 3H), 6.70-7.33 (m,7H), 7.99 (br s, 0.3H), 8.56 (br s, 0.7H), 8.85 (s, 0.7H), 8.91 (s,0.3H); ¹³C NMR (CDCl₃) δ 13.80, 22.32, 29.79, 30.66, 31.00, 31.29,31.69, 32.10, 38.98, 39.49, 39.94, 40.37, 40.90, 43.14, 43.71, 44.13,46.26, 51.98, 55.73, 57.03, 59.91, 60.56, 115.01, 115.16, 121.01,121.96, 124.82, 125.63, 126.15, 127.37, 127.84, 131.07, 131.25, 134.38,135.11, 139.78, 157.93, 158.09, 160.11, 163.45, 166.70, 166.84, 169.09,169.69; ES-MS m/z 582.6 (M+H). Anal. Calcd. for C₃₀H₃₉N₅O₃S₂·0.3CH₂Cl₂:C, 59.93; H, 6.57; N, 11.53. Found: C, 60.10; H, 6.85; N, 11.30.

Example 60

Compound 60 4,6-Dimethyl-pyrimidine-5-carboxylic acid[3-(4-{[2-(3-methoxy-phenylsulfanyl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide

To a solution of 3-methoxybenzenethiol (33 mg, 0.23 mmol) and NEt₃ (0.03ml, 0.24 mmol) in CHCl₃ (2 ml) was added4,6-dimethyl-pyrimidine-5-carboxylic acid(3-{4-[(2-chloro-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide(see EXAMPLE 58) (55 mg, 0.11 mmol). The mixture was stirred at 61° C.for 15 h. The mixture was diluted with CH₂Cl₂ (10 ml) and saturatedaqueous NaHCO₃ (15 ml). The layers were separated and the aqueous wasfurther extracted with CH₂Cl₂ (2×10 ml). The combined organic layer wasdried (Na₂SO₄), filtered and concentrated under reduced pressure. Thecrude material was purified by flash column chromatography on silica gel(9:1, CH₂Cl₂/MeOH) to afford COMPOUND 60 as a white solid (40 mg, 63%).¹H NMR (CDCl₃) δ 0.75-2.20 (m, 12H), 2.25-2.80 (m, 12H), 3.25-3.45 (m,1H), 3.58 (s, 2H), 3.76 (s, 6H), 4.70-3.80 (m, 3H), 6.70-7.33 (m, 7H),7.99 (br s, 0.3H), 8.56 (br s, 0.7H), 8.85 (s, 0.7H), 8.91 (s, 0.3H);¹³C NMR (CDCl₃) δ 13.82, 22.33, 29.84, 30.73, 31.27, 31.66, 32.10,36.46, 37.27, 37.86, 40.00, 40.45, 41.06, 43.22, 43.67, 44.04, 52.02,52.20, 55.69, 57.09, 60.00, 60.65, 113.25, 115.53, 116.03, 121.11,121.62, 122.35, 122.86, 125.77, 126.17, 127.49, 127.57, 130.18, 130.36,131.27, 136.51, 139.64, 157.93, 158.11, 160.15, 163.46, 166.67, 168.78,169.37; ES-MS m/z 582.4 (M+H). Anal. Calcd. for C₃₆H₃₉N₅O₃S₂·0.6CH₂Cl₂:C, 58.09; H, 6.40; N, 11.07. Found: C, 58.00; H, 6.50; N, 10.87.

Example 61

Compound 61 4,6-Dimethyl-pyrimidine-5-carboxylic acid[3-(4-{[2-(1-acetyl-piperidin-4-yl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide

Following general procedure E: a solution of4,6-dimethyl-pyrimidine-5-carboxylic acid(3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (41 mg,0.1 mmol), 4-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester(50 mg, 0.22 mmol), EDCI (39 mg, 0.20 mmol), HOBT (27 mg, 0.20 mmol),and DIPEA (0.05 ml, 0.3 mmol) in CH₂Cl₂ (2 ml) was stirred overnight.Purification of the crude product by column chromatography on silica gel(CH₂Cl₂/MeOH, 9:1) afforded4-{[(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-carbamoyl]-methyl}-piperidine-1-carboxylicacid tert-butyl ester (50 mg, 80%).

Using general procedure C, the above obtained compound was treated withTFA (1 ml) in CH₂Cl₂ (1 ml). Following purification the material wasimmediately dissolved in CH₂Cl₂ (2 ml) at rt. NaHCO₃ (13 mg, 0.15 mmol)was added, followed by acetyl chloride (7.2 mg, 0.09 mmol). The mixturewas stirred at rt for 5 h and was then washed with 1N NaOH (3×4 ml) togive COMPOUND 61 (45 mg, 100%) as a colorless foam (mixture ofrotamers). ¹H NMR (CDCl₃) δ 0.75-4.60 (m, 39H), 6.91-6.95 (m, 2.8H),7.18-7.33 (m, 1H), 7.91 (s, 0.1H), 8.68 (s, 0.3H), 8.88 (dd, 0.8H); ¹³CNMR (CDCl₃) δ 13.79, 21.83, 22.32, 29.87, 30.80, 30.98, 31.85, 32.08,32.39, 32.92, 33.23, 33.41, 39.81, 40.03, 40.29, 40.83, 42.04, 43.01,43.82, 44.28, 46.93, 51.67, 52.08, 56.13, 59.80, 60.92, 120.92, 121.67,125.83, 126.14, 127.27, 127.76, 131.31, 140.03, 140.56, 157.86, 158.07,163.51, 166.65, 169.10, 171.19, 172.34; ES-MS m/z 591 (M+Na).

Example 62

Compound 62 4,6-Dimethyl-pyrimidine-5-carboxylic acid(3-{4-[(3-pyridin-4-yl-propionyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-amide

Using general procedure A, 4-amino-1-Boc-piperidine (481 mg, 2.40 mmol)and 3-thiophenecarboxaldehyde (228 mg, 2.03 mmol) gave4-[(thiophen-3-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butylester as a yellow oil (425 mg, 1.43 mmol, 71%). ¹H NMR (CDCl₃) δ1.22-1.36 (m, 3H), 1.45 (s, 9H), 1.80-1.90 (m, 2H), 2.67 (tt, 1H,J=10.1, 3.9 Hz), 2.74-2.86 (m, 2H), 3.85 (s, 2H), 3.95-4.10 (m, 2H),7.04 (dd, 1H, J=4.8, 1.5 Hz), 7.11-7.14 (m, 1H), 7.29 (dd, 1H, J=5.0,2.9 Hz).

A solution of 4-pyridinecarboxaldehyde (333 mg, 3.11 mmol) and(carboethoxy-methylene)triphenylphosphorane (1.19 g, 3.42 mmol) intoluene (8.0 ml) was stirred at 90° C. under nitrogen for 3 hours. Oncecooled, the solvent was removed under reduced pressure, the crudeproduct was acidified with 1M HCl (25 ml) and the solution was washedwith Et₂O (25 ml×2). The aqueous solution was made basic with 1M NaOHand extracted with CH₂Cl₂ (25 ml×2). The combined organic solution wasdried (Na₂SO₄), filtered and concentrated under reduced pressure, giving(E)-3-pyridin-4-yl-acrylic acid ethyl ester as a white solid (238 mg,1.34 mmol, 43%). ¹H NMR (CDCl₃) δ 1.35 (t, 3H, J=7.2 Hz), 4.29 (q, 2H,J=7.2 Hz), 6.59 (d, 1H, J=16.2 Hz), 7.37 (d, 2H, J=6.1 Hz), 7.60 (d, 1H,J=16.2 Hz), 8.66 (d, 2H, J=6.1 Hz).

A mixture of the unsaturated ester (235 mg, 1.33 mmol) and 10% Pd/C (50%wet with H₂O, 175 mg, 0.08 mmol) in EtOAc (10 ml) was stirred under H₂(1 atm) for 1.5 hours. The mixture was filtered with suction through apad of Celite®, washing with EtOAc. The filtrate was concentrated underreduced pressure and the residue was purified by flash columnchromatography on silica (CH₂Cl₂/Et₂O, 4:1) giving3-pyridin-4-yl-propionic acid ethyl ester as a yellow oil (179 mg, 1.00mmol, 75%). ¹H NMR (CDCl₃) δ 1.23 (t, 3H, J=7.2 Hz), 2.64 (t, 2H, J=7.6Hz), 2.95 (t, 2H, J=7.6 Hz), 4.13 (q, 2H, J=7.2 Hz), 7.13 (d, 2H, J=6.2Hz), 8.50 (d, 2H, J=6.2 Hz).

A solution of the ethyl ester (179 mg, 1.00 mmol) and 10M NaOH (2.0 ml,20 mmol) in MeOH (5.0 ml) was stirred at 50° C. for 17 hours. Oncecooled, the pH was adjusted to 6 and the solvent was evaporated underreduced pressure. The solid residue was triturated with MeOH until no UVactive material remained in the residue. The solution was concentrated,giving the crude carboxylic acid as a mixture with excess NaCl (390 mg).

Using general procedure E, the above acid and4-[(thiophen-3-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butylester (212 mg, 0.72 mmol) gave the amide as a yellow oil (214 mg, 0.50mmol, 70%).

Using general procedure C, the tert-butyl carbamate (214 mg, 0.50 mmol)gave N-piperidin-4-yl-3-pyridin-4-yl-N-thiophen-3-ylmethyl-propionamideas a yellow oil (62.3 mg, 0.19 mmol, 38%).

Using general procedure B, the piperidine (62.3 mg, 0.19 mmol) and2-(3-oxo-butyl)-isoindole-1,3-dione (108 mg, 0.50 mmol) gave the desiredtertiary amine as a white foam (47.5 mg, 0.090 mmol, 47%).

Using general procedure D, the phthalimide gaveN-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-3-pyridin-4-yl-N-thiophen-3-ylmethyl-propionamideas a cloudy, yellow oil (31.3 mg, 0.078 mmol, 87%).

A solution of the primary amine (31.3 mg, 0.078 mmol),4,6-dimethylpyrimidine-5-carboxylic acid (15 mg, 0.099 mmol), EDCI (21mg, 0.11 mmol), HOBT (19 mg, 0.14 mmol) and NMM (20 μL, 0.18 mmol) inDMF (0.50 ml) was stirred at room temperature for 17.5 hours. Thereaction was diluted with saturated aqueous NaHCO₃ (20 ml) and extractedwith CH₂Cl₂ (15 ml×3). The combined organic solution was dried (Na₂SO₄),filtered and concentrated under reduced pressure. Purification by flashcolumn chromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 19:1:0.13) gaveCOMPOUND 62 as a white foam (22.1 mg, 0.041 mmol, 53%). ¹H NMR (CDCl₃) δ0.76-1.04 (m, 2H), 0.96 (d, 3H, J=6.6 Hz), 1.15-1.79 (m, 6H), 1.99-3.01(m, 7H), 2.48 (s, 6H), 3.23-4.46 (m, 5H), 6.81-6.85 and 6.93-6.96 (m,1H), 6.88 and 7.04 (d, 1H, J=5.3 Hz), 7.00 and 7.13 (d, 2H, J=5.7 Hz),7.149 and 7.31 (dd, 1H, J=5.0, 3.2 Hz), 7.92 and 8.73 (br. s, 1H), 8.42and 8.47 (d, 2H, J=5.7 Hz), 8.87 and 8.91 (s, 1H). ¹³C NMR (CDCl₃) δ13.37, 21.88, 29.47, 30.35, 30.43, 30.44, 34.03, 40.11, 42.54, 43.19,51.38, 51.67, 60.38, 120.45, 123.91, 125.65, 126.90, 130.93, 139.42,149.68, 150.13, 157.45, 163.08, 166.15, 171.80. ESI-MS m/z 535 (MH)⁺.Anal. Calcd. for C₂₉H₃₈N₆O₂S·0.3CH₂Cl₂: C, 62.82; H, 6.94; N, 15.00.Found: C, 63.06; H, 7.24; N, 14.74.

Example 63

Compound 63 4,6-Dimethyl-pyrimidine-5-carboxylic acid[3-(4-{[2-(pyridin-4-ylsulfanyl)-thioacetyl]-thiophen-3-ylmethyl-amino}-piperidin-1-yl)-butyl]-amide

Using general procedure E,4-[(thiophen-3-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butylester (200 mg, 0.68 mmol) and 4-pyridylthioacetic acid (230 mg, 1.36mmol) in CH₂Cl₂ (5 ml) afforded4-{[2-(pyridin-4-ylsulfanyl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidine-1-carboxylicacid tert-butyl ester as a white solid (290 mg, 95%).

Using general procedure F,4-{[2-(pyridin-4-ylsulfanyl)-acetyl]-thiophen-3-ylmethyl-amino}-piperidine-1-carboxylicacid tert-butyl ester (290 mg, 0.65 mmol) in toluene (5 ml) andLawsson's reagent (171 mg, 0.42 mmol) afforded4-{[2-(pyridin-4-ylsulfanyl)-thioacetyl]-thiophen-3-ylmethyl-amino}-piperidine-1-carboxylicacid tert-butyl ester as a white solid (145 mg, 48%).

Using general procedure C,4-{[2-(pyridin-4-ylsulfanyl)-thioacetyl]-thiophen-3-ylmethyl-amino}-piperidine-1-carboxylicacid tert-butyl ester (145 mg, 0.31 mmol) afforded the desired amine.

Using general procedure B followed by general procedure D, the crudematerial (140 mg, quantitative) affordedN-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-2-(pyridin-4-ylsulfanyl)-N-thiophen-3-ylmethyl-thioacetamideas a colorless oil (60 mg, 45% over three steps).

Using general procedure E,N-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-2-(pyridin-4-ylsulfanyl)-N-thiophen-3-ylmethyl-thioacetamide(60 mg, 0.138 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (32mg, 0.20 mmol) afforded COMPOUND 63 as a white solid (60 mg, 77%). ¹HNMR (CDCl₃) mixture of rotamers: δ 0.75-1.24 (m, 5H), 1.25-2.85 (m,20H), 3.25-5.50 (m, 6H), 6.80-7.40 (m, 5H), 7.65 (br s, 0.25H),7.30-7.50 (m, 2H), 8.88 (br s, 0.7H), 8.95 (s, 0.3H); ¹³C NMR (CDCl₃) δ13.93, 22.37, 28.97, 29.84, 31.13, 31.79, 31.94, 39.75, 40.37, 43.57,43.68, 44.12, 46.93, 48.17, 51.76, 59.70, 60.00, 60.56, 62.02, 121.57,122.05, 122.18, 125.86, 126.04, 127.07, 128.16, 131.29, 136.70, 137.25,149.81; 150.00, 157.95, 158.16, 163.55, 166.62, 199.0; ES-MS m/z 569.5(M+H). Anal. Calcd. for C₂₈H₃₆N₆OS₃·0.6CH₂Cl₂: C, 55.43; H, 6.05; N,13.56. Found: C, 55.25; H, 6.12; N, 13.46.

Example 64

Compound 642,6-Dichloro-N—((R)-3-{4-[(2-methoxy-thioacetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

To a solution of2,6-dichloro-N—((R)-3-{4-[(2-methoxy-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide(COMPOUND 39) (257 mg, 0.49 mmol) in toluene (5 ml) was added Lawesson'sreagent (128 mg, 0.32 mmol). The mixture was refluxed at 125° C. for 2.5h and concentrated in vacuo. The crude product was purified bypreparative TLC (ether, 3% MeOH, 1% NH₄OH) and two products (the mono-and bis-thioamides) were isolated. The mono-thioamide COMPOUND 64 (84mg, 32% yield) was a white solid and a mixture of rotational isomers. ¹HNMR (CDCl₃) δ 0.97-0.99 (d, 3H, J=6 Hz), 1.17-1.45 (m, 1H), 1.50-1.65(m, 2H), 1.65-1.81 (m, 2H), 2.10-2.25 (m, 1H), 2.36 and 2.38 (s, total3H), 2.47-2.57 (m, 1H), 2.70-2.90 (m, 3H), 3.24-3.37 (m, 1H), 3.38 and3.46 (s, total 3H), 3.73-3.86 (m, 1H), 4.30 and 4.44 (s, total 2H), 4.44and 4.49 (s, total 2H), 4.68-4.98 (m, 1H), 5.31-5.48 (m, 1H), 6.96-7.00(m, 1H), 7.15 (m, 1H), 7.15-7.16 (m, 1H), 7.33-7.36 (m, 1H), 7.97 and8.56 (br s, total 1H); ES-MS m/z 543 (M+H).

Example 65

Compound 652,6-Dichloro-N—((R)-3-{4-[(2-hydroxy-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

To a solution of2,6-dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(177 mg, 0.39 mmol) in 1,2-dichloroethane (5 ml) was added DIPEA (0.35ml, 2.01 mmol) followed by acetoxyacetyl chloride (0.1 ml, 0.93 mmol)and the reaction stirred at 65° C. for 3 h. The solution was cooled,treated with saturated aqueous NaHCO₃ (25 ml) and extracted with CH₂Cl₂(3×15 ml). The combined organic extracts were dried (Na₂SO₄), filtered,and concentrated. Purification of the crude material by columnchromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 96:4:0 then 88:10:2)provided the desired amide (88 mg, 41%) as a brown oil. To a solution ofthe acetate from above (80 mg, 0.14 mmol) in MeOH (5 ml) was added K₂CO₃(67 mg, 0.49 mmol) and the reaction stirred overnight. The mixture wasconcentrated then diluted with CH₂Cl₂ (25 ml) and saturated aqueousNaHCO₃ (20 ml). The aqueous layer was extracted with CH₂Cl₂ (2×10 ml)and the combined organic extracts were dried (Na₂SO₄), filtered, andconcentrated. Purification of the crude material by columnchromatography on silica gel (CH₂Cl₂/MeOH, 96:4 then 9:1) affordedCOMPOUND 65 (48 mg, 59%) as a pale yellow foam and a mixture of tworotational isomers. ¹H NMR (CDCl₃) δ 0.94-0.99 (m, 3H), 1.19-1.43 (m,2H), 1.50-1.73 (m, 5H), 2.09-2.14 (m, 1H), 2.35 and 2.38 (s, total 3H),2.51-2.57 (m, 1H), 2.70-2.85 (m, 3H), 3.19-3.40 (m, 1H), 3.75-3.82 (m,1H), 3.98-4.28 (m, 5H), 6.93-6.95 (m, 1H), 7.02-7.05 (m, 1H), 7.12-7.15(m, 1H), 7.23-7.35 (m, 1H), 7.86-7.88 and 8.57-8.60 (m, total 1H); ES-MSm/z 513 (M+H). Anal. Calcd. for C₂₃H₃₀N₄O₃SCl₂·0.3H₂O: C, 53.24; H,5.94; N, 10.80. Found: C, 53.27; H, 5.88; N, 10.54.

Example 66

Compound 662,6-Dichloro-4-methyl-N—((R)-3-{4-[(2-methylamino-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-nicotinamide

Following general procedure E: to a stirred solution of2,6-dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(62 mg, 0.137 mmol), (tert-butoxycarbonyl-methyl-amino)-acetic acid (28mg, 0.159 mmol), HOBt (24 mg, 0.177 mmol) and DIPEA (59 μL, 0.34 mmol)in DMF (3 ml) was added EDCI (34 mg, 0.177 mmol). The reaction wasstirred at rt overnight under N₂ pressure. The resultant crude product(88 mg) was used in the next step.

Following general procedure C: the Boc-protected amine from above (88mg) provided COMPOUND 66 (49 mg, 68%). ¹H NMR (CDCl₃) δ 0.97-0.99 (m,4H), 1.92-1.25 (m, 2H), 1.49-1.54 (m, 2H), 1.64-1.76 (m, 2H), 2.15 (m,1H), 2.35-2.39 (m, 6H), 2.45-2.54 (m, 1H), 2.71-2.84 (m, 3H), 3.25-3.41(m, 3H), 3.81-3.81 (m, 1H), 3.99-4.00 (m, 2H), 4.37 (m, 1H), 6.97-7.03(m, 2H), 7.13 (s, 1H), 7.33-7.35 (m, 1H), 8.78 (br s, 1H); ES-MS m/z 526(M+H).

Example 67

Compound 676-Chloro-2,4-dimethyl-N—((R)-3-{4-[(2-1H-tetrazol-5-yl-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-nicotinamide

6-Chloro-N-(3-{4-[(2-cyano-acetyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide(0.080 g, 0.16 mmol) was dissolved in iso-propanol (3 ml) and dilutedwith water (6 ml) (Demke and Sharpless, JOC 2001, 66, 7945-50). To themilky solution were added ZnBr₂ (0.036 g, 0.16 mmol) and NaN₃ (0.011 g,0.18 mmol) and the resulting mixture was refluxed for 16 h. The crudereaction mixture was dry-loaded onto silica gel and purified via columnchromatography (MeCN/MeOH/NH₄OH, 7:2:1, v/v/v) to yield COMPOUND 67(0.039 g, 45%) as a white solid. ¹H NMR (CD₃OD) (mixture of rotamers) δ1.22 (m, 3H), 1.46 (m, 1H), 1.70-1.94 (m, 5H), 2.36 (s, 3H), 2.50 (s,3H), 2.54-2.75 (m, 2H), 2.98 (m, 2H), 3.05 (m, 1H), 3.50 (m, 2H), 4.00(s) and 4.17 (s) (total 2H), 4.06 (m) and 4.41 (m) (total 1H), 4.55 (s)and 4.69 (s) (total 2H), 7.07 (m, 1H), 7.23 (s) and 7.34 (s) (total 1H),7.28 (s, 1H), 7.33 (m) and 7.50 (m) (total 1H); ES-MS m/z 589 (M+2Na).

Example 68

Compound 686-Chloro-2,4-dimethyl-N—[(R)-3-(4-{[2-(2-oxo-oxazolidin-3-yl)-acetyl]-thiazol-4-ylmethyl-amino}-piperidin-1-yl)-butyl]-nicotinamide

Sodium azide (0.770 g, 11.9 mmol) was added to a solution of4-bromomethyl-thiazole (1.22 g, 9.17 mmol) in N,N′-dimethylformamide (15ml) and the resulting pale yellow solution was stirred at 50° C. for 16hours. Standard basic workup gave the crude product as a white solid.The crude solid was dissolved in methanol (30 ml), treated with 10% Pd/C(0.40 g) and placed under 1 atm. H₂ for 12 hours. The mixture wasfiltered through Celite®, the cake was washed with MeOH and the combinedfiltrate was concentrated under reduced pressure to give a tan liquid.Purification by column chromatography on silica gel (CH₂C₂/MeOH/NH₄OH,86:12:2, v/v/v) afforded 4-aminomethyl-thiazole (0.540 g, 52%) as a paleyellow liquid. ¹H NMR (CDCl₃) δ 1.96 (s, 2H), 4.04 (s, 2H), 7.14 (s,1H), 8.78 (s, 1H).

Using general procedure A, [3-(4-oxo-piperidin-1-yl)-butyl]-carbamicacid tert-butyl ester (0.780 g, 2.88 mmol), 4-aminomethyl-thiazole(0.328 g, 2.88 mmol), sodium triacetoxyborohydride (1.22 g, 5.76 mmol)and acetic acid (0.2 ml, cat.) in methylene chloride (50 ml) at 25° C.for 16 hours gave the crude product as a pale yellow oil.

Using general procedure C gave[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-thiazol-4-ylmethyl-amine(0.54 g, 70%; 2-steps) as a pale yellow oil.

Following general procedure E: to a stirred solution of[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-thiazol-4-ylmethyl-amine(0.320 g. 1.19 mmol), EDCI (0.252 g, 1.31 mmol) and HOBt (0.177 g, 1.31mmol) in DMF (5 ml) was added 6-chloro-2,4-dimethyl-nicotinic acid(0.243 g, 1.31 mmol) followed by DIPEA (343 μL, 1.78 mmol) and theresulting mixture was stirred at 25° C. for 16 hours. Standard workupand purification by column chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH, 93:5:2) afforded6-chloro-2,4-dimethyl-N-(3-{4-[(thiazol-4-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(0.42 g, 81%) as a colorless oil.

Following general procedure E: to a stirred solution of6-chloro-2,4-dimethyl-N-(3-{4-[(thiazol-4-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(0.094 g, 0.22 mmol), EDCI (0.045 g, 0.24 mmol) and HOBt (0.032 g, 0.24mmol) in DMF (5 ml) was added (2-oxo-oxazolidin-3-yl)-acetic acid (seeEXAMPLE 24) (0.034 g, 0.42 mmol) followed by DIPEA (62 μL, 0.32 mmol)and the resulting mixture was stirred at 25° C. for 16 hours. Standardworkup and purification by column chromatography on silica gel(Et₂O/MeOH/NH₄OH, 83:15:2) afforded COMPOUND 68 (0.067 g, 55%) as awhite foam. ¹H NMR (CDCl₃) (mixture of rotamers) δ 0.94 (d+m, 4H), 1.08(m, 1H), 1.51-1.75 (m, 4H), 2.11 (br t, 1H), 2.33 (s, 3H), 2.49 (br t,1H), 2.52 (s, 3H), 2.65 (m, 1H), 2.78 (m, 2H), 3.27 (m, 1H), 3.71-3.83(m, 3H), 4.08-4.19 (m, 4H), 4.37 (m, 3H), 6.92 (s) and 7.10 (s) (total1H), 7.31 (s) and 7.38 (s) (total 1H), 8.03 (br s) and 8.50 (br s)(total 1H), 8.65 (s) and 8.75 (s) (total 1H); ES-MS m/z 563 (M+H).

Example 69

Compound 69 4,6-Dimethyl-pyrimidine-5-carboxylic acid(3-{4-[benzyl-(2-cyclohexyl-thioacetyl)-amino]-piperidin-1-yl}-butyl)-amide

Using general procedure E, 4-benzylamino-piperidine-1-carboxylic acidtert-butyl ester (300 mg, 1.03 mmol) and cyclohexylacetic acid (161 mg,1.13 mmol) afforded4-[benzyl-(2-cyclohexyl-acetyl)-amino]-piperidine-1-carboxylic acidtert-butyl ester as a white solid (360 mg, 85%).

Using general procedure F, A solution of the above amide (142 mg, 0.34mmol) and Lawesson's reagent (90 mg, 0.22 mmol) in toluene (3 ml)afforded4-[benzyl-(2-cyclohexyl-thioacetyl)-amino]-piperidine-1-carboxylic acidtert-butyl ester (119 mg, 82%).

Using general procedure C with the above substrate (119 mg, 0.28 mmol),then general procedure B with the resulting amine and2-(3-oxo-butyl)-isoindole-1,3-dione (120 mg, 0.55 mmol) and then usinggeneral procedure D affordedN-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-N-benzyl-2-cyclohexyl-thioacetamide(45 mg, 41% over 3 steps).

Using general procedure E, the above amine (45 mg, 0.11 mmol) and4,6-dimethylpyrimidine-5-carboxylic acid (19 mg, 0.12 mmol) affordedCOMPOUND 69 as a white solid (50 mg, 85%). ¹H NMR (CDCl₃) mixture ofrotomers: δ 0.75-1.40 (m, 9H), 1.41-2.96 (m, 18H), 2.51 (s, 6H),3.25-3.43 (m, 1H), 3.62-3.87 (m, 1H), 4.20-4.88 and 4.80-5.13 (m, 2H),5.56-5.67 (m, 1H), 7.11 (d, 1H, J=7.2 Hz), 7.17-7.40 (m, 3H), 8.34-8.43(m, 1H), 8.95 (s, 1H); ¹³C NMR (CDCl₃) δ 13.9, 22.4, 26.6, 29.2, 30.1,31.1, 32.1, 33.3, 33.8, 39.7, 40.2, 40.4, 43.6, 44.3, 49.8, 51.2, 51.9,52.0, 59.6, 60.6, 60.8, 126.0, 126.3, 126.7, 127.1, 128.0, 128.7, 129.3,131.3, 136.8, 158.0, 158.2, 163.6, 166.7; ES-MS m/z 536 (M+H). Anal.Calcd. for C₃₁H₄₅N₅OS·0.2CH₂Cl₂: C, 67.79; H, 8.28; N, 12.67. Found: C,67.74; H, 8.27; N, 12.52.

Example 70

Compound 70 4,6-Dimethyl-pyrimidine-5-carboxylic acid(3-{4-[(2-cyclohexyl-acetyl)-(3-methyl-benzyl)-amino]-piperidin-1-yl}-butyl)-amide

Using general procedure A, 3-methylbenzylamine (30 μL, 0.23 mmol) and4,6-dimethylpyrimidine-5-carboxylic acid[3-(4-oxo-piperidin-1-yl)-butyl]-amide (66 mg, 0.22 mmol) afforded4,6-dimethyl-pyrimidine-5-carboxylic acid{3-[4-(3-methyl-benzylamino)-piperidin-1-yl]-butyl}-amide (65 mg, 72%).

Using general procedure E, the above amine (65 mg, 0.16 mmol) andcyclohexylacetic acid (25 mg, 0.17 mmol) afforded COMPOUND 70 as a whitesolid (27 mg, 32%). ¹H NMR (CDCl₃) mixture of rotomers: δ 0.74-1.40 (m,9H), 1.47-1.96 (m, 1H), 2.00-2.95 (m, 7H), 2.35 (s, 3H), 2.50 (s, 6H),3.24-3.42 (m, 1H), 3.60-4.12 (m, 3H), 4.36-4.52 (m, 1H), 6.80-6.98 (m,2H), 7.06 (d, 1H, J=7.2 Hz), 7.22 (t, 1H, J=7.8 Hz), 8.53-8.68 (m, 1H),8.94 (s, 1H); ¹³C NMR (CDCl₃) δ 13.8, 21.8, 22.3, 26.6, 26.7, 30.0,31.0, 31.4, 31.8, 32.3, 33.6, 34.0, 35.5, 39.9, 40.4, 41.6, 43.8, 44.3,44.8, 46.3, 51.8, 52.2, 56.3, 59.9, 60.7, 123.1, 123.9, 126.7, 127.6,128.2, 128.5, 128.9, 138.7, 158.0, 163.5, 166.7, 173.8; ES-MS m/z 535(M+H+1). Anal. Calcd. for C₃₂H₄₇N₅O₂·0.2CH₂Cl₂: C, 70.22; H, 8.67; N,12.72. Found: C, 70.58; H, 8.90; N, 12.51.

Example 71

Compound 71 4,6-Dimethyl-pyrimidine-5-carboxylic acid(3-{4-[(3-methylbenzyl)-(2-tetrahydropyran-4-yl-thioacetyl)-amino]-piperidin-1-yl}-butyl)-amide

Using general procedure A, 3-methylbenzylamine (198 μL, 1.58 mmol) and1-Boc-4-piperidone (300 mg, 1.51 mmol) afforded4-(3-methylbenzylamino)-piperidine-1-carboxylic acid tert-butyl ester asa white solid (375 mg, 82%).

Using general procedure E,4-(3-methylbenzylamino)-piperidine-1-carboxylic acid tert-butyl ester(365 mg, 1.2 mmol) and (tetrahydropyran-4-yl)-acetic acid (173 mg, 1.2mmol) afforded4-[(3-methylbenzyl)-(2-tetrahydropyran-4-yl-acetyl)-amino]-piperidine-1-carboxylicacid tert-butyl ester as a white solid (217 mg, 42%).

Using general procedure F, the above amide (217 mg, 0.5 mmol) andLawesson's reagent (132 mg, 0.32 mmol) in toluene (8 ml) afford4-[(3-methylbenzyl)-(2-tetrahydropyran-4-yl-thioacetyl)-amino]-piperidine-1-carboxylicacid tert-butyl ester (164 mg, 74%).

Using general procedure C with the above substrate (164 mg, 0.37 mmol),then general procedure B with the resulting amine and2-(3-oxo-butyl)-isoindole-1,3-dione (160 mg, 0.73 mmol) and then usinggeneral procedure D affordedN-[1-(3-amino-1-methylpropyl)-piperidin-4-yl]-N-(3-methylbenzyl)-2-(tetrahydro-pyran-4-yl)-thioacetamide(121 mg, 79% over 3 steps).

Using general procedure E,N-[1-(3-amino-1-methylpropyl)-piperidin-4-yl]-N-(3-methylbenzyl)-2-(tetrahydro-pyran-4-yl)-thioacetamide(40 mg, 0.10 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (16 mg,0.11 mmol) afforded COMPOUND 71 as a white solid (40 mg, 75%). ¹H NMR(CDCl₃) mixture of rotomers: δ 0.80-1.29 (m, 4H), 0.97 (d, 3H, J=6.6Hz), 1.38-2.07 (m, 7H), 2.11-2.84 (m, 7H), 2.35 (s, 3H), 2.50 (s, 6H),3.24-3.48 (m, 3H), 3.71-3.84 (m, 1H), 3.89 (d, 2H, J=11.4 Hz), 4.15-4.37(m, 2H), 5.52-5.67 (m, 1H), 6.85-6.94 (m, 2H), 7.08 (d, 1H, J=7.5 Hz),7.23 (t, 1H, J=8.5 Hz), 8.33-8.45 (m, 1H), 8.94 (s, 1H); ¹³C NMR (CDCl₃)δ 11.9, 19.9, 20.4, 27.1, 28.0, 29.2, 30.0, 30.2, 30.9, 31.4, 34.8,37.6, 38.3, 41.7, 42.3, 47.8, 47.9, 49.8, 50.1, 57.5, 57.7, 58.1, 58.5,58.8, 66.3, 120.9, 121.6, 124.5, 125.3, 125.9, 126.6, 126.8, 127.2,129.3, 134.5, 134.7, 136.4, 137.2, 156.0, 156.2, 161.5, 164.7; ES-MS m/z552 (M+H). Anal. Calcd. for C₃₁H₄₅N₅O₂S·0.2CH₂Cl₂: C, 65.89; H, 8.05; N,12.31. Found: C, 65.56; H, 8.00; N, 12.19.

Example 72 was prepared in a similar manner as Example 70 except that2-methoxybenzylamine was used in lieu of 3-methylbenzylamine.

Example 72

Compound 72 4,6-Dimethyl-pyrimidine-5-carboxylic acid(3-{4-[(2-cyclohexyl-acetyl)-(2-methoxy-benzyl)-amino]-piperidin-1-yl}-butyl)-amide

Mixture of rotomers: ¹H NMR (CDCl₃) δ 0.77-1.26 (m, 9H), 1.52-1.99 (m,13H), 2.10-3.83 (m, 5H), 2.48 (s, 6H,), 3.26-3.44 (m, 1H), 3.74-3.93 (m,1H), 3.94 (s, 3H), 4.13-4.18 (m, 2H), 4.36-4.52 (m, 1H), 6.80-7.00 (m,3H), 7.19-7.22 (m, 1H), 7.75-7.77 (m, 1H), 8.85 (m, 1H); ¹³C NMR (CDCl₃)δ 13.8, 22.3, 26.6, 29.9, 30.5, 31.2, 31.9, 32.9, 33.6, 34.0, 35.5,39.7, 40.1, 41.5, 42.1, 44.3, 44.6, 51.9, 52.1, 55.6, 56.4, 58.6, 59.7,110.2, 120.6, 126.6, 126.8, 127.6, 128.4, 130.9, 156.6, 157.9, 163.3,167.0, 174.1; ES-MS m/z 550 (M+H). Anal. Calcd. forC₃₂H₄₇N₅O₃·0.3CH₂Cl₂: C, 67.44; H, 8.34; N, 12.17. Found: C, 67.12; H,8.54; N, 12.03.

Example 73

Compound 736-Chloro-N—((R)-3-{4-[(3,3-dimethyl-butyryl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

To a solution of tert-butylacetic acid (63 μL, 0.50 mmol) and DMF (3drops) in methylene chloride (4 ml) was added oxalyl chloride (115 μL,1.32 mmol) and the resulting orange solution was stirred at 25° C. for 3hours. The solvent was removed in vacuo to give an orange residue.(3-{4-[(4-Methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (0.125 g, 0.33 mmol) and triethylamine (115 μL,0.83 mmol) dissolved in tetrahydrofuran (5 ml) were added to the flaskcontaining the orange residue and the resulting mixture was stirred at50° C. for 12 hours. Standard basic workup gave the crude product as anorange oil. Purification by column chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH, 93:5:2, v/v/v) afforded(3-{4-[(3,3-dimethyl-butyryl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (0.095 g, 60%) as a tan oil.

Following general procedure C(3-{4-[(3,3-dimethyl-butyryl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (0.095 g, 0.20 mmol) gave the crude amine.Following general procedure E: to a stirred solution of the amine, EDCI(0.042 g, 0.22 mmol) and HOBt (0.030 g, 0.22 mmol) in DMF (5 ml) wasadded 6-chloro-2,4-dimethyl-nicotinic acid (0.044 g, 0.22 mmol) followedby DIPEA (192 μL, 1.10 mmol) and the resulting mixture was stirred at25° C. for 16 hours. Standard workup and purification by columnchromatography on silica gel (Et₂O/MeOH/NH₄OH, 88:10:2) affordedCOMPOUND 73 (0.082 g, 78%) as a white foam. ¹H NMR (CDCl₃) (mixture ofrotamers) δ 0.95-1.16 (m, 14H), 1.51-1.75 (m, 3H), 2.02 (m, 1H), 2.13(m, 1H), 2.29 (s+m, 5H), 2.49 (s, 3H), 2.72-2.79 (m, 3H), 3.25-3.42 (m,1H), 3.56-3.75 (m, 2H), 4.07-4.28 (m, 2H), 4.55 (m, 1H), 6.89-7.11 (m)and 7.76 (br s) (total 3H), 8.11-8.46 (m, 2H); ES-MS m/z 542 (M+H).

Example 74

Compound 746-Chloro-2,4-dimethyl-N—((R)-3-{4-[(4-methyl-pyridin-3-ylmethyl)-(tetrahydro-pyran-4-carbonyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide

4-Methylnicotinic acid (2.50 g, 14.4 mmol), EDCI (4.14 mg, 21.6 mmol)and HOBt (2.92 mg, 21.6 mmol) were combined in DMF (1 ml) and CH₂Cl₂ (75ml) to give a pale yellow solution. To this solution was added ammoniumchloride (2.31 g, 43.2 mmol) followed by DIPEA (12.5 ml, 72.0 mmol) andthe resulting mixture was stirred at room temperature for 16 hours. Thesolvent was removed in vacuo and diluted with saturated aqueous NaHCO₃(50 ml) and CH₂Cl₂ (50 ml). The solution was then basicified to pH ˜14with 10N NaOH. The phases were separated and the aqueous layer wasextracted with CH₂Cl₂ (5×50 ml). The combined organic extracts weredried (Na₂SO₄), filtered and concentrated under reduced pressure. Thecrude material was purified by flash column chromatography on silica gel(94:5:1, CH₂Cl₂/MeOH/NH₄OH) to generate 4-methyl-nicotinamide as anoff-white solid (0.95 g, 48%). ¹H-NMR (CDCl₃) δ 2.53 (s, 3H), 7.20 (d,1H, J=4 Hz), 8.53 (d, 1H, J=4 Hz), 8.69 (s, 1H).

To a solution of 4-methylnicotinamide (0.93 g, 6.84 mmol) in THF (100ml) was added borane in THF (1M, 20.5 ml, 20.5 mmol) and the solutionwas heated at 60° C. for 72 hours. The reaction mixture was then cooledto room temperature followed by the addition of 9M HCl (67 ml). Thissolution was subsequently heated at 65° C. for 2.5 hours. The solutionwas cooled to room temperature and concentrated under reduced pressurefollowed by the addition of saturated aqueous NaHCO₃ (100 ml). Thesolution was basicified with 10N NaOH to pH ˜13 and then extracted withCH₂Cl₂ (5×50 ml). The combined organic extracts were dried (Na₂SO₄),filtered and concentrated under reduced pressure. The crude material waspurified by flash column chromatography on silica gel (44:5:1,CH₂Cl₂/MeOH/NH₄OH) to generate C-(4-methyl-pyridin-3-yl)-methylamine asa white solid (0.32 g, 38%). ¹H-NMR (CDCl₃) δ 1.67 (s, 2H), 2.37, (s,3H), 3.90 (s, 2H), 7.08 (d, 1H, J=3 Hz), 8.38 (d, 1H, J=3 Hz), 8.48 (s,1H).

Following general procedure A: to a stirred solution ofC-(4-methyl-pyridin-3-yl)-methylamine (0.78 g, 6.36 mmol) in CH₂Cl₂ (15ml) were added (R)-[3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acidtert-butyl ester (1.85 g, 7.00 mmol), glacial AcOH (0.36 ml, 6.36 mmol)and NaBH(OAc)₃ (1.89 g, 8.90 mmol) and the resultant solution wasstirred at room temperature for 16 hours. Standard workup andpurification by flash column chromatography on silica gel (94:5:1,Et₂O/MeOH/NH₄OH) generated(R)-(3-{4-[(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester as an off-white solid (1.81 g, 76%). ¹H-NMR(CDCl₃) δ 0.94 (d, 3H, J=6 Hz), 1.20 (d, 1H, J=6 Hz), 1.39 (s+m, 13H),1.63 (m, 7H), 1.94 (d, 2H, J=9 Hz), 2.11 (t, 1H, J=11 Hz), 2.43 (s, 3H),2.48 (m, 2H), 2.72 (m, 3H), 3.14 (m, 1H), 3.38 (m, 1H), 3.49 (s, 3H),3.79 (s, 2H), 6.11 (br s, 1H), 7.07 (d, 1H, J=6 Hz), 8.36 (d, 2H, J=6Hz), 8.43 (s, 1H).

To a stirred suspension of a tetrahydro-pyran-4-carboxylic acid (55.4mg, 0.43 mmol) in CH₂Cl₂ (5 ml) were added DMF (2 drops) followed byoxalyl chloride (0.10 ml, 1.06 mmol) and the resultant mixture wasstirred at room temperature for 1.5 hours. The mixture was concentratedunder reduced pressure and the acid chloride was dried in vacuo for 45minutes. To the acid chloride was added a solution of[3-(4-benzylamino-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester(0.10 g, 0.27 mmol) and triethylamine (0.10 ml, 0.66 mmol) in THF (5 ml)and the mixture was stirred at 50° C. for 16 hours. The mixture wasconcentrated under reduced pressure and then diluted with CH₂Cl₂ (30 ml)and 10 ml saturated aqueous NaHCO₃. The phases were separated and theaqueous layer was extracted with CH₂Cl₂ (5×30 ml). The organic layer wasdried (Na₂SO₄), filtered and concentrated under reduced pressure. Thecrude material was purified by flash column chromatography on silica gel(96:3:1, CH₂Cl₂/MeOH/NH₄OH) to generate(R)-(3-{4-[(4-methyl-pyridin-3-ylmethyl)-(tetrahydro-pyran-4-carbonyl)-amino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester as a crude yellow oil (0.10 g).

Following general procedureC(R)-(3-{4-[(4-methyl-pyridin-3-ylmethyl)-(tetrahydro-pyran-4-carbonyl)-amino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (0.10 g) gave the free amine. Following generalprocedure E: to a stirred solution of the amine, EDCI (56.2 mg, 0.29mmol) and HOBt (39.6 mg, 0.29 mmol) in DMF (7 ml) was added6-chloro-2,4-dimethylnicotinic acid hydrochloride salt (65.0 mg, 0.29mmol) followed by DIPEA (255.0 μL, 1.46 mmol) and the resulting mixturewas stirred at room temperature for 16 hours. Standard workup andpurification by preparative TLC (91:8:1, CH₂C₂/MeOH/NH₄OH) affordedCOMPOUND 74 as a white foam (29.8 mg, 20%). ¹H NMR (CDCl₃) δ 0.98 (m,3H), 1.61 (m, 5H), 2.02 (m, 2H), 2.32 (m, 6H), 2.48 (s, 3H), 2.84 (m,2H), 3.22 (t, 1H, J=12 Hz), 3.46 (m, 2H), 3.66 (m, 1H), 3.94 (m, 1H),4.28 (m, 1H), 6.98-7.14 (m, 2H), 7.71-8.42 (m, 2H); ES-MS m/z 556 (M+H),578 (M+Na).

Example 75

Compound 75N—((R)-3-{4-[Benzyl-(4-methyl-tetrahydro-pyran-4-carbonyl)-amino]-piperidin-1-yl}-butyl)-6-chloro-2,4-dimethyl-nicotinamide

Following general procedure A: to a stirred solution of benzylamine.(0.38 ml, 3.43 mmol) in CH₂Cl₂ (20 ml) were added(R)-[3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester(1.00 g, 3.77 mmol), glacial AcOH (0.20 ml, 3.43 mmol) and NaBH(OAc)₃(1.02 g, 4.80 mmol) and the resultant solution was stirred at roomtemperature for 16 hours. Standard workup and purification by flashcolumn chromatography on silica gel (94:5:1, CH₂Cl₂MeOH/NH₄OH) generated(R)-[3-(4-benzylamino-piperidin-1-yl)-butyl]-carbamic acid tert-butylester as an off-white solid (1.30 g, 100%). ¹H-NMR (CDCl₃) δ 0.92 (d,3H, J=8 Hz), 1.39 (m, 2H), 1.44 (s, 9H), 1.67 (m, 3H), 1.93 (d, 2H, J=13Hz), 2.09 (t, 3H, J=11 Hz), 2.46 (m, 2H), 2.74 (m, 3H), 3.06 (m, 1H),3.31 (m, 1H), 3.81 (s, 2H), 6.02 (br s, 1H), 7.24 (m, 1H), 7.31 (m, 4H).

To a stirred suspension of (4-methyl-tetrahydro-pyran-4-yl)-acetic acid(140.0 mg, 0.89 mmol) in CH₂Cl₂ (10 ml) were added DMF (4 drops)followed by oxalyl chloride (0.26 ml, 2.95 mmol) and the resultantmixture was stirred at room temperature for 1.5 hours. The mixture wasconcentrated under reduced pressure and the acid chloride was dried invacuo for 45 minutes. To the acid chloride was added a solution of(R)-[3-(4-benzylamino-piperidin-1-yl)-butyl]-carbamic acid tert-butylester (262.8 mg, 0.74 mmol) and triethylamine (0.26 ml, 1.85 mmol) inTHF (10 ml) and the mixture was stirred at 50° C. for 16 hours. Themixture was concentrated under reduced pressure and then diluted withCH₂Cl₂ (30 ml) and 10 ml saturated aqueous NaHCO₃. The phases wereseparated and the aqueous layer was extracted with CH₂Cl₂ (5×30 ml). Theorganic layer was dried (Na₂SO₄), filtered and concentrated underreduced pressure. The crude material was purified by flash columnchromatography on silica gel (97:2:1, CH₂Cl₂MeOH/NH₄OH) to generate(R)-[3-(4-{benzyl-[2-(4-methyl-tetrahydro-pyran-4-yl)-acetyl]-amino}-piperidin-1-yl)-butyl]-carbamicacid tert-butyl ester as a crude yellow oil (315.0 mg).

Using general procedure C,(R)-[3-(4-{benzyl-[2-(4-methyl-tetrahydro-pyran-4-yl)-acetyl]-amino}-piperidin-1-yl)-butyl]-carbamicacid tert-butyl ester (315.0 mg) gave the free amine. Following generalprocedure E: to a stirred solution of the amine (85.0 mg), EDCI (94.7mg, 0.23 mmol) and HOBt (31.5 mg, 0.23 mmol) in DMF (5 ml) was added6-chloro-2,4-dimethylnicotinic acid hydrochloride salt (51.7 mg, 0.23mmol) followed by DIPEA (185.0 μL, 1.06 mmol) and the resulting mixturewas stirred at room temperature for 16 hours. Standard workup andpurification by preparative TLC (91:8:1, CH₂Cl₂/MeOH/NH₄OH) affordedCOMPOUND 75 as a white foam (70.6 mg, 59%). ¹H NMR (CDCl₃) δ 0.77 (m,1H), 0.96 (m, 3H), 1.10 (s, 3H), 1.47 (m, 2H), 1.68 (m, 2H), 2.15 (m,2H), 2.30 (s, 3H), 2.52 (s, 3H), 2.62 (m, 1H), 2.78 (m, 2H), 3.25 (m,1H), 3.62 (m, 4H), 3.72 (m, 1H), 3.84 (m, 1H), 4.02 (m, 2H), 4.48 (m,1H), 7.02 (s, 1H), 7.20 (m, 2H), 7.35 (m, 3H), 8.75 (m, 1H); ES-MS m/z569 (M+H), 591 (M+Na).

Examples 76 to 88 were prepared following the scheme below wherein R¹NCOis defined in the table and R² is as shown in the individual examples.

TABLE 4

Example R¹NCO 76* cyclohexyl isocyanate 77* cyclohexane methylisocyanate 78* 3,4-methylenedioxy phenyl isocyanate 79* Cycloheptylisocyanate 80* 6-isocyanato-1,4-benzodioxane 81* 3-methoxyphenylisocyanate 82* 3-fluoro-phenyl isocyanate 83* 4-methoxyl-phenylisocyanate 84* 2-fluoro-phenyl isocyanate 85* 2-methoxyl-phenylisocyanate 86  3,4-difluoro-phenyl isocyanate 87 4-methylsulfanyl-phenyl isocyanate 88  4-cyanophenyl isocyanate *=racemic

Example 76

Compound 76N-{3-[4-(1-Benzyl-3-cyclohexyl-ureido)-piperidin-1-yl]-butyl}-6-chloro-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.80-0.87 (m, 3H), 0.98 (d, 3H, J=6.6 Hz),1.03-1.07 (m, 1H), 1.18-1.30 (m, 2H), 1.44-1.54 (m, 4H), 1.67-1.76 (m,6H), 2.13-2.20 (m, 1H), 2.26 (s, 3H), 2.49 (s, 3H), 2.57-2.60 (m, 1H),2.67-2.70 (m, 1H), 2.79-2.83 (m, 2H), 3.20-3.30 (m, 1H), 3.49-3.55 (m,1H), 3.75 (m, 2H), 3.82-3.87 (m, 1H), 4.00 (d, 1H, J=7.8 Hz), 4.30 (m,1H), 6.93 (s, 1H), 7.28-7.29 (m, 3H), 7.34-7.39 (m, 2H), 8.00 (br s,1H); ES-MS m/z 554 (M+H).

Example 77

Compound 77N-{3-[4-(1-Benzyl-3-cyclohexylmethyl-ureido)-piperidin-1-yl]-butyl}-6-chloro-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.57-0.69 (m, 2H), 0.79-0.83 (m, 1H), 0.99(d, 3H, J=6.6 Hz), 1.03-1.07 (m, 3H), 1.12-1.22 (m, 2H), 1.34-1.38 (m,2H), 1.48-1.57 (m, 4H), 1.69-1.78 (m, 3H), 2.13-2.21 (m, 1H), 2.26 (s,3H), 2.49 (s, 3H), 2.54-2.61 (m, 1H), 2.68-2.71 (m, 1H), 2.79-2.83 (m,2H), 2.89-2.96 (m, 2H), 3.21-3.29 (m, 1H), 3.76 (s, 2H), 3.83-3.89 (m,1H), 4.14-4.17 (m, 1H), 4.32 (m, 1H), 6.92 (s, 1H), 7.28-7.31 (m, 3H),7.37-7.40 (m, 2H), 8.84 (br s, 1H); ES-MS m/z 568 (M+H).

Example 78

Compound 78N-{3-[4-(3-Benzo[1,3]dioxol-5-yl-1-benzyl-ureido)-piperidin-1-yl]-butyl}-6-chloro-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.88-0.93 (m, 1H), 0.99 (d, 3H, J=6.6 Hz),1.05-1.10 (m, 1H), 1.50-1.56 (s, 2H), 1.75-1.78 (m, 3H), 2.16-2.24 (m,1H), 2.28 (s, 3H), 2.50 (s, 3H), 2.60-2.64 (m, 1H), 2.71-2.74 (m, 1H),2.83-2.85 (m, 2H), 2.84-2.91 (m, 3H), 3.27-3.31 (m, 1H), 3.84-3.91 (m,3H), 5.88 (s, 2H), 5.97 (s, 1H), 6.28-6.31 (m, 1H), 6.59-6.62 (d, 1H,J=8.1 Hz), 6.84 (d, 1H, J=1.8 Hz), 6.95 (s, 1H), 7.34-7.45 (m, 5H), 8.75(br s, 1H); ES-MS m/z 592 (M+H).

Example 79

Compound 79N-{3-[4-(1-Benzyl-3-cycloheptyl-ureido)-piperidin-1-yl]-butyl}-6-chloro-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.78-0.83 (m, 1H), 0.97-1.03 (m, 1H), 0.99(d, 3H, J=6.6 Hz), 1.16-1.22 (m, 2H), 1.33-1.34 (m, 6H), 1.44-1.54 (m,3H), 1.57 (s, 1H), 1.64-1.78 (m, 5H), 2.13-2.20 (m, 1H), 2.26 (s, 3H),2.49 (s, 3H), 2.53-2.60 (m, 1H), 2.67-2.71 (m, 1H), 2.79-2.82 (m, 2H),3.22-3.29 (m, 1H), 3.72-3.77 (m, 3H), 3.84-3.88 (m, 1H), 4.04-4.06 (d,1H, J=7.5 Hz), 4.30-4.34 (m, 1H), 6.93 (s, 1H), 7.28-7.29 (m, 2H),7.37-7.39 (m, 2H), 8.84 (br s, 1H); ES-MS m/z 566 (M+H).

Example 80

Compound 80N-(3-{4-[1-Benzyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ureido]-piperidin-1-yl}-butyl)-6-chloro-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.84-0.94 (m, 1H), 0.98 (d, 3H, J=6.6 Hz),1.00-1.08 (m, 1H), 1.50 (m, 1H), 1.68-1.78 (m, 3H), 2.16-2.24 (m, 1H),2.28 (s, 3H), 2.50 (s, 3H), 2.57-2.64 (m, 1H), 2.71-2.74 (m, 1H),2.83-2.85 (m, 2H), 3.23-3.31 (m; 1H), 3.86-3.91 (m, 3H), 4.16-4.18 (m,4H), 4.34 (m, 1H), 5.92 (s, 1H), 6.48-6.52 (m, 1H), 6.66-6.69 (m, 2H),6.95 (s, 1H), 7.33-7.42 (m, 5H), 8.78 (br s, 1H); ES-MS m/z 628 (M+Na).

Example 81

Compound 81N-(3-{4-[1-Benzyl-3-(3-methoxy-phenyl)-ureido]-piperidin-1-yl}-butyl)-6-chloro-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.93 (m, 1H), 0.99 (d, 3H, J=4.5 Hz), 1.11(m, 1H), 1.50 (m, 1H), 1.77-1.79 (m, 3H), 2.22-2.25 (m, 1H), 2.29 (s,3H), 2.50 (s, 3H), 2.62 (m, 1H), 2.71 (m, 1H), 2.83 (m, 2H), 3.29 (m,1H), 3.74 (s, 3H), 3.87-3.93 (m, 3H), 4.36 (m, 1H), 6.14 (s, 1H),6.48-6.54 (m, 2H), 6.94 (d, 2H, J=1.8 Hz), 7.03-7.09 (m, 1H), 7.34-7.43(m, 5H), 8.74 (br s, 1H); ES-MS m/z 578 (M+H).

Example 82

Compound 82N-(3-{4-[1-Benzyl-3-(3-fluoro-phenyl)-ureido]-piperidin-1-yl}-butyl)-6-chloro-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.91 (m, 1H), 0.96 (d, 3H, J=6.6 Hz), 1.01(m, 1H), 1.50 (m, 1H), 1.77 (m, 3H), 2.28 (m, 1H), 2.29 (s, 3H), 2.50(s, 3H), 2.63 (m, 1H), 2.75 (m, 1H), 2.86 (m, 2H), 3.30 (m, 1H),3.85-3.95 (m, 3H), 4.35 (m, 1H), 6.19 (s, 1H), 6.62-6.68 (m, 2H), 6.95(s, 2H), 7.06-7.13 (m, 2H), 7.35-7.47 (m, 6H); ES-MS m/z 566 (M+H).

Example 83

Compound 83N-(3-{4-[1-Benzyl-3-(4-methoxy-phenyl)-ureido]-piperidin-1-yl}-butyl)-6-chloro-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.87-0.92 (m, 1H), 0.98 (d, 3H, J=6.6 Hz),1.05-1.23 (m, 1H), 1.49-1.55 (m, 1H), 1.68-1.78 (m, 3H), 2.16-2.23 (m,1H), 2.28 (s, 3H), 2.50 (s, 3H), 2.56-2.63 (m, 1H), 2.70-2.74 (m, 1H),2.83-2.85 (m, 2H), 3.23-3.31 (m, 1H), 3.73 (s, 3H), 3.85-3.99 (m, 3H),4.35 (m, 1H), 5.97 (s, 1H), 6.72-6.77 (m, 2H), 6.95-7.02 (m, 3H),7.31-7.45 (m, 5H), 8.77 (br s, 1H); ES-MS m/z 578 (M+H).

Example 84

Compound 84N-(3-{4-[1-Benzyl-3-(2-fluoro-phenyl)-ureido]-piperidin-1-yl}-butyl)-6-chloro-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.93-1.15 (m, 5H), 1.55 (m, 1H), 1.78-1.82(m, 3H), 2.23 (m, 1H), 2.28 (s, 3H), 2.50 (s, 3H), 2.62-2.66 (m, 1H),2.74 (m, 1H), 2.85 (m, 2H), 3.27-3.30 (m, 1H), 3.85-4.00 (m, 3H), 4.35(m, 1H), 6.42 (m, 1H), 6.88-6.93 (m, 3H), 7.01-7.06 (m, 1H), 7.31-7.44(m, 5H), 7.98-8.04 (m, 1H), 8.65 (br s, 1H); ES-MS m/z 566 (M+H).

Example 85

Compound 85N-(3-{4-[1-Benzyl-3-(2-methoxy-phenyl)-ureido]-piperidin-1-yl}-butyl)-6-chloro-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.91-0.95 (m, 1H), 0.99 (d, 3H, J=6.3 Hz),1.09-1.12 (m, 1H), 1.57 (m, 1H), 1.78-1.82 (m, 3H), 2.23 (m, 1H), 2.27(s, 3H), 2.50 (s, 3H), 2.63 (m, 1H), 2.67-2.72 (m, 1H), 2.84 (m, 2H),3.29-3.32 (m, 1H), 3.47 (s, 3H), 3.84-3.86 (m, 1H), 3.89 (s, 2H), 4.38(m, 1H), 6.67-6.71 (m, 1H), 6.85-6.93 (m, 4H), 7.28-7.43 (m, 5H),8.04-8.07 (m, 1H), 8.73 (br s, 1H); ES-MS m/z 576 (M+H).

Example 86

Compound 86N—((R)-3-{4-[1-Benzyl-3-(3,4-difluoro-phenyl)-ureido]-piperidin-1-yl}-butyl)-6-fluoro-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.92-0.96 (m, 1H), 0.99 (d, 3H, J=6.6 Hz),1.08-1.14 (m, 1H), 1.51 (m, 1H), 1.71-1.79 (m, 3H), 2.18-2.26 (m, 1H),2.31 (s, 3H), 2.47 (s, 3H), 2.58-2.66 (m, 1H), 2.73-2.77 (m, 1H),2.85-2.88 (m, 2H), 3.25-3.32 (m, 1H), 3.84-3.91 (m, 3H), 4.34 (m, 1H),6.05 (s, 1H), 6.43 (s, 1H), 6.50-6.53 (m, 1H), 6.88-6.97 (m, 1H),7.16-7.23 (m, 1H), 7.30-7.33 (d, 2H, J=7.2 Hz), 7.37-7.39 (d, 1H, J=6.9Hz), 7.42-7.47 (m, 2H), 8:72 (br S, 1H); ES-MS m/z 568 (M+H).

Example 87

Compound 87N—((R)-3-{4-[1-Benzyl-3-(4-methylsulfanyl-phenyl)-ureido]-piperidin-1-yl}-butyl)-6-chloro-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 1.38 (d, 3H, J=6.6 Hz), 1.94-2.05 (m, 4H), 2.19-2.32(m, 4H), 2.23 (s, 3H), 2.41 (s, 3H), 2.44 (s, 3H), 2.87-2.95 (m, 1H),3.04-3.12 (m, 1H), 3.30-3.40 (m, 1H), 3.46-3.56 (m, 2H), 4.50 (s, 2H),4.69-4.80 (m, 1H), 6.30 (s, 1H), 6.93 (s, 1H), 7.05 (d, 2H, J=9 Hz),7.15 (d, 2H, J=9 Hz), 7.26-7.41 (m, 5H), 7.74 (br s, 1H); ES-MS m/z 594(M+H).

Example 88

Compound 88N—((R)-3-{4-[1-Benzyl-3-(4-cyano-phenyl)-ureido]-piperidin-1-yl}-butyl)-6-chloro-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.95-0.99 (m, 1H), 1.01 (d, 3H, J=6 Hz), 1.11-1.19 (m,1H), 1.49-1.56 (m, 1H), 1.76-1.84 (m, 2H), 2.22-2.27 (m, 1H), 2.28 (s,3H), 2.50 (s, 3H), 2.64-2.69 (m, 1H), 2.72-2.85 (m, 3H), 3.22-3.28 (m,1H). 3.81-3.92 (m, 1H), 3.95 (s, 2H), 4.26-4.32 (m, 1H), 6.34 (s, 1H),6.94 (s, 1H), 7.17 (d, 2H, J=9 Hz), 7.34-7.49 (m, 7H), 8.69 (br s, 1H);ES-MS m/z 573 (M+H).

Examples 89 and 90 were prepared following the scheme below whereinR¹NH₂ is defined in the table and R² is as shown in the individualexamples.

TABLE 5

Ex- ample R¹NH₂ 89* piperonyl- amine 90  4- amino- pyridine *= racemic

Example 89

Compound 89N-{3-[4-(3-1,3-Benzodioxol-5-ylmethyl-1-benzyl-ureido)-piperidin-1-yl]-butyl}-6-chloro-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.77-1.09 (m, 2H), 0.97 (d, 3H, J=6.6 Hz), 1.47-1.56(m, 1H), 1.66-1.78 (m, 3H), 2.17 (br t, 1H, J=11.4 Hz), 2.27 (s, 3H),2.49 (s, 3H), 2.52-2.61 (m, 1H), 2.65-2.84 (m, 3H), 3.20-3.31 (m, 1H),3.79-3.90 (m, 3H), 4.18 (d, 2H, J=5.4 Hz), 4.26-4.37 (m, 1H), 4.44 (t,1H, J=5.7 Hz), 5.90 (s, 2H), 6.46-6.50 (m, 2H), 6.64 (d, 1H, J=7.8 Hz),6.94 (s, 1H), 7.24-7.37 (m, 5H), 8.76 (d, 1H, J=6.0 Hz); ES-MS m/z 606(M+H).

Example 90

Compound 90N—{(R)-3-[4-(1-Benzyl-3-pyridin-4-yl-ureido)-piperidin-1-yl]-butyl}-6-chloro-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.96-0.98 (m, 1H), 1.01 (d, 3H, J=6 Hz), 1.12-1.21 (m,1H), 1.48-1.53 (m, 1H), 1.74-1.81 (m, 3H), 2.21-2.25 (m, 1H), 2.28 (s,3H), 2.50 (s, 3H), 2.64-2.71 (m, 1H), 2.75-2.92 (m, 3H), 3.22-3.30 (m,1H), 3.87-3.93 (m, 1H), 3.96 (s, 2H), 4.27-4.35 (m, 1H), 6.30 (s, 1H),6.94 (s, 1H), 7.01-7.05 (m, 2H), 7.34-7.49 (m, 5H), 8.30-8.34 (m, 2H),8.63 (br s, 1H); ES-MS m/z 550 (M+H).

Examples 91 and 92 were prepared following the scheme below whereinR¹CNO is defined in the table and R² is as shown in the individualexamples.

TABLE 6

Example R¹CNO 91 isopropylisocyanate 92 cyclohexylisocyanate

Example 91

Compound 916-Chloro-N—((R)-3-{4-[3-isopropyl-1-(4-methyl-pyridin-3-ylmethyl)-ureido]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.95-1.03 (m, 10H), 1.09 (m, 1H), 1.59 (m,1H), 1.75 (m, 4H), 2.20 (m, 1H), 2.29 (s, 3H), 2.36 (s, 3H), 2.49 (s,3H), 2.51 (m, 1H), 2.63-2.78 (m, 3H), 3.34 (m, 1H), 3.68-3.94 (m, 3H),4.02 (s, 2H), 4.17 (br t, 1H), 6.97 (s, 1H), 7.10 (d, 1H, J=4.5 Hz),7.68 (br t, 1H), 8.33 (s, 1H), 8.39 (d, 1H, J=4.5 Hz); ES-MS m/z 529(M+H).

Example 92

Compound 922-Chloro-N—((R)-3-{4-[3-cyclohexyl-1-(4-methyl-pyridin-3-ylmethyl)-ureido]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.85-0.95 (m, 2H), 0.96-1.07 (d+m, 5H),1.29 (m, 3H), 1.50 (m, 3H), 1.72 (br m, 5H), 2.22 (br t, 1H), 2.34 (s,3H), 2.39 (s, 3H), 2.58 (br t, 1H), 2.70-2.81 (m, 3H), 3.34 (m, 1H),3.56 (m, 1H), 3.75-3.86 (m, 2H), 3.97 (s, 2H), 4.20 (br t, 1H), 6.91 (d,1H, J=4.5 Hz), 7.12 (d, 1H, J=4.5 Hz), 7.87 (d, 1H, J=4.5 Hz), 8.20 (brs, 1H), 8.29 (s, 1H), 8.41 (d, 1H, J=4.5 Hz); ES-MS m/z 555 (M+H).

Example 93

Compound 932,6-Dichloro-N—((R)-3-{4-[1-(6-cyano-pyridin-2-ylmethyl)-3-ethyl-ureido]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

Sodium azide (0.280 g, 4.32 mmol) was added to a solution of6-bromomethyl-pyridine-2-carbonitrile (0.610 g, 2.88 mmol) in DMF (12ml) and the resulting pale yellow solution was stirred at rt for 16 h.Standard basic workup gave the crude product as a tan solid inquantitative yield (0.501 g). The crude solid was dissolved in MeOH (15ml), treated with 10% Pd/C (0.050 g) and placed under 40 psi H₂ on aParr shaker for 30 minutes (Note: it is imperative that this reductionis stopped at 30 minutes or reduction of the nitrile also occurs). Themixture was filtered through Celite®, the cake was washed with MeOH andthe combined filtrate was concentrated under reduced pressure to give ayellow oil. Purification by column chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH, 83:15:2, v/v/v) afforded6-aminomethyl-pyridine-2-carbonitrile (0.178 g, 46%) as a whitecrystalline solid. ¹H NMR (CDCl₃) δ 1.96 (br s, 2H), 4.02 (s, 2H), 7.53(d, 1H, J=9.0 Hz), 7.59 (d, 1H, J=9.0 Hz), 7.80 (t, 1H, J=9.0 Hz).

Using general procedure A, [3-(4-oxo-piperidin-1-yl)-butyl]-carbamicacid tert-butyl ester (0.361 g, 1.34 mmol),6-aminomethyl-pyridine-2-carbonitrile (0.178 g, 1.34 mmol), sodiumtriacetoxyborohydride (0.425 g, 2.01 mmol) and acetic acid (0.2 ml,cat.) in CH₂Cl₂ (15 ml) at rt for 16 h gave the crude product as a paleyellow oil. Purification by column chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH, 86:12:2, v/v/v) afforded(3-{4-[(6-cyano-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (0.400 g, 77%) as a colorless oil. ¹H NMR (CDCl₃)δ 0.93 (d, 3H, J=6.0 Hz), 1.40 (s+m, 13H), 1.65 (m, 1H), 1.92 (m, 2H),2.13 (br t, 1H, J=9.0 Hz), 2.45 (m, 2H), 2.69-2.81 (m, 3H), 3.07 (m,1H), 3.30 (m, 1H), 3.97 (s, 2H), 5.95 (br s, 1H), 7.56 (d, 1H, J=9.0Hz), 7.59 (d, 1H, J=9.0 Hz), 7.77 (t, 1H, J=7.5 Hz).

(3-{4-[(6-Cyano-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (0.067 g, 0.17 mmol) and ethyl isocyanate (20 μL,0.25 mmol) were combined in 1,2-dichloroethane (5 ml) and the resultingmixture was stirred at 55° C. for 16 h. The solvent was removed in vacuoand the crude residue was purified by column chromatography on silicagel (CH₂Cl₂:MeOH:NH₄OH, 93:6:1, v/v/v) to give(3-{4-[1-(6-cyano-pyridin-2-ylmethyl)-3-ethyl-ureido]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (0.075 g, 95%) as a white foam. ¹H NMR (CDCl₃) δ0.93 (d, 3H, J=6.0 Hz), 1.12 (t, 3H, J=7.5 Hz), 1.40 (s+m, 13H), 1.65(m, 1H), 1.92 (m, 2H), 2.18 (br t, 1H, J=9.0 Hz), 2.52 (m, 2H),2.69-2.85 (m, 3H), 3.09 (m, 1H), 3.21-3.33 (m, 3H), 4.12 (m, 1H), 4.44(s, 2H), 5.33 (br s, 1H), 5.95 (br s, 1H), 7.57 (d, 1H, J=9.0 Hz), 7.61(d, 1H, J=9.0 Hz), 7.83 (t, 1H, J=7.5 Hz).

(3-{4-[1-(6-cyano-pyridin-2-ylmethyl)-3-ethyl-ureido]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (0.075 g, 0.16 mmol) was dissolved in a 3:1mixture of CH₂Cl₂ and TFA and the mixture was stirred at rt for 1 h. Thesolvent was removed in vacuo and the resulting brown oil pumped in vacuo(high vacuum system) for 2 h. The resulting amine, EDCI (0.035 g, 0.18mmol) and HOBt (0.024 g, 0.18 mmol) were combined in DMF (5 ml) to givea pale yellow solution. To this solution was added2,6-dichloro-4-methyl-nicotinic acid (synthesized according to reportedpatent procedure WO 03/027112) (0.037 g, 0.18 mmol) followed by DIPEA(188 μL, 1.08 mmol) and the resulting mixture was stirred at 25° C. for16 h. Standard workup according to general procedure E gave the crudeproduct as a tan oil. Purification by column chromatography on silicagel (Et₂O/MeOH/NH₄OH, 90:8:2, v/v/v) afforded COMPOUND 93 (0.048 g, 54%)as a white foam. ¹H NMR (CDCl₃) δ 0.98 (m+d, 4H), 1.12 (t, 3H, J=7.5Hz), 1.23 (m, 1H), 1.61 (m, 3H), 1.75 (m, 1H), 2.15 (br t, 1H), 2.42 (s,3H), 2.54 (br t, 1H), 2.73 (m, 1H), 2.83-2.88 (m, 2H), 3.23 (m, 2H),3.33 (m, 1H), 3.87 (m, 1H), 3.89 (dd, 2H, J=15.0, 4.5 Hz), 5.65 (br t,1H), 7.20 (s, 1H), 7.59 (d, 1H, J=9.0 Hz), 7.62 (d, 1H, J=9.0 Hz), 7.88(t, 1H, J=9.0 Hz), 8.96 (br d, 1H); ES-MS m/z 546 (M+H). Anal. Calcd.for C₂₆H₃₃N₇O₂Cl₂·0.3CH₄O·0.5H₂O: C, 55.90; H, 6.28; N, 17.35. Found: C,55.83; H, 6.19; N, 17.27.

Examples 94 and 95 were prepared following the scheme below whereinR¹NH₂ is defined in the table and R² is as shown in the individualexamples.

TABLE 7

Example R¹NH₂ 94 tetrahydro-pyran-4-ylamine hydrochloride 95 methylaminehydrochloride

Example 94

Compound 942,6-Dichloro-N—((R)-3-{4-[1-(6-cyano-pyridin-2-ylmethyl)-3-(tetrahydro-pyran-4-yl)-ureido]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 1.00 (d+m, 4H), 1.13 (m, 1H), 1.33-1.62 (m,3H), 1.78 (m, 2H), 1.90 (m, 2H), 2.13 (br t, 1H), 2.43 (s, 3H), 2.53 (brt, 1H), 2.75-2.89 (m, 3H), 3.39-3.48 (m, 3H), 3.82-3.99 (m, 6H), 6.00(br s, 1H), 7.20 (s, 1H), 7.63 (d+d, 2H, J=6.0 Hz), 7.90 (t, 1H, J=6.0Hz), 8.99 (br s, 1H); ES-MS m/z 602 (M+H).

Example 95

Compound 952,6-Dichloro-N—((R)-3-{4-[1-(6-cyano-pyridin-2-ylmethyl)-3-methyl-ureido]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

White solid. ¹H NMR (CDCl₃) δ 0.92-1.26 (m, 2H), 0.98 (d, 3H, J=6 Hz),1.49-1.87 (m, 5H), 2.11-2.18 (m, 1H), 2.42 (s, 2H), 2.50-2.57 (m, 1H),2.73-2.89 (m, 6H), 3.25-3.38 (m, 1H), 3.77-4.02 (m, 4H), 5.43 (br s,1H), 7.20 (s, 1H), 7.58-7.63 (m, 2H), 7.83-7.89 (m, 1H), 8.87 (br s,1H); ES-MS m/z 554 (M+Na).

Examples 96 to 107 were prepared following the scheme below whereinR¹NH₂ and R²CNO are as defined in the table and R³ is as shown in theindividual examples.

TABLE 8

Example R¹NH₂ R²CNO  96 n- butyl- amine ethyl iso- cyanate  97 2-methoxy- ethyl- amine 4- fluoro- phenyl iso- cyanate  98 2- methyl-butyl- amine 4- fluoro- phenyl iso- cyanate  99 n- hexyl- amine ethyliso- cyanate 100 2- (ethylthio) ethyl- amine hydro- chloride ethyl iso-cyanate 101 n- propyl- amine 4- fluoro- phenyl iso- cyanate 102 isoamyl-amine 4- fluoro- phenyl iso- cyanate 103 amyl- amine 4- fluoro- phenyliso- cyanate 104 3- (methyl- thio)- propyl- amine 4- fluoro- phenyl iso-cyanate 105 n- hexyl- amine 4- fluoro- phenyl iso- cyanate 106 cyclo-pentyl- methyl- amine 4- fluoro- phenyl iso- cyanate 107 cyclo- hexyl-methyl- amine 4- fluoro- phenyl- iso- cyanate

Example 96

Compound 96N—{(R)-3-[4-(1-Butyl-3-ethyl-ureido)-piperidin-1-yl]-butyl}-2,6-dichloro-4-methyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.93-0.99 (m, 7H), 1.10-1.15 (m, 4H),1.17-1.40 (m, 5H), 1.60 (m, 2H), 1.73-1.75 (m, 1H), 2.14-2.17 (m, 1H),2.39 (s, 3H), 2.50-2.61 (m, 3H), 2.73-2.86 (m, 3H), 3.21-3.31 (m, 3H),3.84-3.86 (m, 1H), 4.03 (m, 1H), 4.18 (m, 1H), 7.15 (s, 1H), 8.74 (br s,1H); ES-MS m/z 508 (M+Na).

Example 97

Compound 976-Chloro-N—((R)-3-{4-[3-(4-fluoro-phenyl)-1-(2-methoxy-ethyl)-ureido]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.69-0.89 (m, 1H), 0.92-0.97 (m, 1H), 1.00 (d, 3H, J=6Hz), 1.47-1.53 (m, 1H), 1.69-1.79 (m, 3H), 2.16-2.24 (m, 1H), 2.34 (s,3H), 2.54 (s, 3H), 2.54-2.62 (m, 1H), 2.66-2.95 (m, 5H), 3.21-3.29 (m,1H), 3.43 (br s, 2H), 3.49 (s, 3H), 3.82-3.91 (m, 1H), 3.99-4.13 (m,1H), 6.90-697 (m, 2H), 7.06 (s, 1H), 7.21-7.25 (m, 2H), 8.55 (s, 1H),9.10 (br s, 1H); ES-MS m/z 534 (M+H).

Example 98

Compound 986-Chloro-N—((R)-3-{4-[3-(4-fluoro-phenyl)-1-(2-methyl-butyl)-ureido]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.92-0.98 (m, 9H), 1.00-1.27 (m, 2H), 1.28(m, 1H), 1.48-1.49 (m, 2H), 1.69-1.78 (m, 3H), 2.13-2.20 (m, 2H), 2.33(s, 3H), 2.51 (m, 1H), 2.54 (s, 3H), 2.58-2.63 (m, 1H), 2.71-2.81 (m,4H), 3.33 (m, 1H), 3.83-3.87 (m, 1H), 3.98 (m, 1H), 6.21 (s, 1H),6.98-7.02 (m, 3H), 7.26-7.29 (m, 2H), 8.08 (br s, 1H); ES-MS m/z 548(M+H).

Example 99

Compound 992,6-Dichloro-N—{(R)-3-[4-(3-ethyl-1-hexyl-ureido)-piperidin-1-yl]-butyl}-4-methyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.89-0.99 (m, 9H), 1.09-1.16 (m, 4H),1.21-1.30 (m, 4H), 1.43 (s, 3H), 1.56-1.81 (m, 7H), 2.10 (t, 1H, J=12Hz), 2.38 (s, 3H), 2.52-2.57 (m, 3H), 2.69-2.82 (m, 3H), 2.91-3.03 (m,1H), 3.21-3.33 (m, 3H), 3.81-3.89 (m, 1H), 3.94-4.07 (m, 1H), 4.18-4.25(m, 1H), 7.13 (s, 1H), 8.74 (s, 1H); ES-MS m/z 514 (M+H).

Example 100

Compound 1002,6-Dichloro-N—((R)-3-{4-[3-ethyl-1-(2-ethylsulfanyl-ethyl)-ureido]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

¹H NMR (CDCl₃) δ 0.99 (d, 3H, J=6 Hz), 1.06-1.15 (m, 3H), 1.21-1.29 (m,3H), 1.51-1.84 (m, 6H), 2.09-2.19 (m, 1H), 2.39 (s, 3H), 2.49-2.68 (m,5H), 2.71-2.84 (m, 5H), 3.22-3.37 (m, 3H), 3.77-3.91 (m, 2H), 5.10 (brs, 1H), 7.20 (s, 1H), 8.74 (br s, 1H); ES-MS m/z 540 (M+Na).

Example 101

Compound 1016-Chloro-N—((R)-3-{4-[3-(4-fluoro-phenyl)-1-propyl-ureido]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.90-1.03 (m, 7H), 1.12-1.17 (m, 1H),1.49-1.54 (m, 4H), 1.67-1.73 (m, 2H), 1.75-1.79 (m, 1H), 2.13-2.20 (m,1H), 2.35 (s, 3H), 2.53 (br s, 1H), 2.55 (s, 3H), 2.60-2.86 (m, 5H),3.27-3.34 (m, 1H), 3.86-3.91 (m, 1H), 4.10 (m, 1H), 6.15 (s, 1H),6.95-7.01 (m, 2H), 7.05 (s, 1H), 7.29-7.32 (m, 1H), 8.57 (br d, 1H);ES-MS m/z 518 (M+H).

Example 102

Compound 1026-Chloro-N—((R)-3-{4-[3-(4-fluoro-phenyl)-1-(3-methyl-butyl)-ureido]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.95-1.02 (m, 10H), 1.19-1.24 (m, 1H),1.36-1.44 (m, 2H), 1.55 (m, 1H), 1.59-1.80 (m, 4H), 2.14-2.21 (m, 1H),2.33 (s, 3H), 2.52-2.59 (m, 1H), 2.54 (s, 3H), 2.72-2.85 (m, 5H),3.29-3.37 (m, 1H), 3.83-3.89 (m, 1H), 4.04-4.12 (m, 1H), 6.16 (s, 1H),6.95-7.03 (m, 3H), 7.29-7.33 (m, 2H), 8.18 (br s, 1H); ES-MS m/z 546(M+H).

Example 103

Compound 1036-Chloro-N—((R)-3-{4-[3-(4-fluoro-phenyl)-1-pentyl-ureido]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.95-1.08 (m, 7H), 1.12-1.23 (m, 1H), 1.28-1.42 (m,4H), 1.49-1.58 (m, 3H), 1.65 (br s, 3H), 1.68-1.77 (m, 1H), 2.17-2.22(m, 1H), 2.33 (s, 3H), 2.54 (s, 3H), 2.56-2.82 (m, 5H), 3.24-3.32 (m,1H), 3.85-3.91 (m, 1H), 4.04-4.12 (m, 1H), 6.18 (s, 1H), 6.93-7.02 (m,3H), 7.25-7.32 (m, 1H), 8.44 (br s, 1H); ES-MS m/z 546 (M+H).

Example 104

Compound 104 6-Chloro-N—((R)-3-{4-[3-(4-fluoro-phenyl)-1-(3-methylsulfanyl-propyl)-ureido]-piperidin-1-yl}-butyl)-2,4-dimethylnicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.88-0.93 (m, 1H), 0.99 (d, 3H, J=6.6 Hz),1.08-1.14 (m, 1H), 1.55 (m, 1H), 1.69-1.79 (m, 5H), 2.13 (s, 3H),2.17-2.21 (m, 1H), 2.34 (s, 3H), 2.55 (s, 3H), 2.55-2.66 (m, 3H),2.73-2.87 (m, 5H), 3.29-3.33 (m, 1H), 3.87-3.91 (m, 1H), 4.17 (m, 1H),6.93-6.99 (t, 2H, J=8.7 Hz), 7.05 (s, 1H), 7.39-7.46 (m, 3H), 8.79 (brs, 1H); ES-MS m/z 564 (M+H).

Example 105

Compound 1056-Chloro-N—((R)-3-{4-[3-(4-fluoro-phenyl)-1-hexyl-ureido]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.92-1.01 (m, 7H), 1.13-1.18 (m, 1H), 1.34(br s, 6H), 1.45-1.52 (m, 2H), 1.66-1.78 (m, 4H), 2.13-2.20 (t, 1H,J=10.8 Hz), 2.34 (s, 3H), 2.54 (s, 3H), 2.59-2.85 (m, 6H), 3.31 (m, 1H),3.84-3.91 (m, 1H), 4.09 (m, 1H), 6.16 (s, 1H), 6.95-7.03 (m, 2H),7.03-7.30 (m, 2H), 8.45 (br s, 1H); ES-MS m/z 560 (M+H).

Example 106

Compound 1066-Chloro-N—((R)-3-{4-[1-cyclopentylmethyl-3-(4-fluoro-phenyl)-ureido]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.98 (d, 3H, J=12 Hz), 0.99-1.07 (m, 1H),1.09-1.18 (m, 3H), 1.51-1.92 (m, 1H), 1.94-2.01 (m, 1H), 2.15 (t, 1H,J=12 Hz), 2.33 (s, 3H), 2.51-2.57 (m, 1H), 2.53 (s, 3H), 2.71-2.86 (m,4H), 3.32 (t, 1H, J=12 Hz), 3.86-3.92 (m, 1H), 3.97-4.04 (m, 1H), 6.28(s, 1H), 6.94-7.01 (m, 3H), 7.27-7.32 (m, 2H), 8.30 (br s, 1H); ES-MSm/z 558 (M+H).

Example 107

Compound 1072,6-Dichloro-N—((R)-3-{4-[1-cyclohexylmethyl-3-(4-fluoro-phenyl)-ureido]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

To a solution of cyclohexylmethanol (2.4 ml, 20 mmol) in CH₂Cl₂ (42 ml)was added Et₃N (3.0 ml, 22 mmol). The mixture was cooled to 0° C. whenmesyl chloride (1.7 ml, 22 mmol) was added. It was then stirred at rtfor 30 min, diluted with CH₂Cl₂ (20 ml), washed with 1N NaOH (3×60 ml),dried over Na₂SO₄ and concentrated. The crude methanesulfonic acidcyclohexylmethyl ester (3.50 g, 87%) was a yellow oil and was used inthe next reaction without purification.

To a solution of the above mesylate (3.50 g, 18.2 mmol) in DMF (20 ml)was added NaN₃ (1.8 g, 27.3 mmol). The mixture was stirred at 65° C.overnight, cooled, diluted with H₂O (30 ml) and extracted with 1:1hexanes/ether (2×50 ml). The combined organic layers were washed withsaturated NaCl solution (3×25 ml) to remove residual DMF, dried withmgSO₄ and concentrated. The crude azidomethyl-cyclohexane (2.06 g, 90%)was a yellow oil and was used in the next reaction without purification.

To a solution of the above azide (2.06 g, 14.8 mmol) in MeOH (20 ml) wasadded Pd/C (0.515 g, 25 wt %). The mixture was placed on thehydrogenator for 2 h at 50 psi hydrogen, then filtered through Celite®and concentrated. ¹H NMR and TLC (2:1 hexanes/ethyl acetate) showed twoproducts. Hydrogenation for another 2 h showed the same result. Thecrude cyclohexylmethylamine (1.83 g) was used in the next reactionwithout purification.

COMPOUND 107 was isolated as a yellowish solid. ¹H NMR (CDCl₃) δ0.85-0.92 (m, 2H), 0.98-1.00 (d, 3H, J=6 Hz), 1.18-1.21 (m, 2H),1.24-1.83 (m, 13H), 2.08-2.13 (m, 1H), 2.39 (s, 3H), 2.49-2.62 (m, 1H),2.62-2.77 (m, 2H), 2.77-2.88 (m, 2H), 3.28-3.42 (m, 1H), 3.49 (s, 2H),3.77-3.98 (m, 1H), 6.21 (s, 1H), 6.97-7.03 (m, 2H), 7.13 (s, 1H),7.27-7.29 (m, 2H), 8.37 (br s, 1H); ES-MS m/z 592 (M+H).

Examples 108 and 109 were prepared following the scheme below whereinR¹CHO and R²CNO are as defined in the table and R³ is as shown in theindividual examples.

TABLE 9

Example R¹CHO R²CNO 108 2,2- dimethyl- propionaldehyde 2,3-methylenedioxy phenyl isocyanate 109 tetrahydrofuran- 2- carboxaldehyde4-fluoro- phenyl- isocyanate

Example 108

Compound 108N—((R)-3-{4-[3-1,3-Benzodioxol-4-yl-1-(2,2-dimethyl-propyl)-ureido]-piperidin-1-yl}-butyl)-6-chloro-2,4-dimethyl-nicotinamide

¹H NMR (CD₃OD) δ 0.9-1.1 (m, 13H), 1.70-2.20 (m, 7H), 2.30 (s, 3H),2.50-2.55 (m, 4H), 2.80-3.00 (m, 5H), 3.20-3.40 (m, 2H), 3.70-3.85 (m,1H), 5.92, (s, 2H), 6.28 (s, 1H), 6.57 (dd, 1H, J=9, 3 Hz), 6.70 (d, 1H,J=9 Hz), 6.98 (s, 1H), 7.04 (s, 1H), 7.70 (s, 1H); ES-MS m/z 572 (M+1).

Example 109

Compound 1096-Chloro-N—((R)-3-{4-[3-(4-fluoro-phenyl)-1-(tetrahydro-furan-2-ylmethyl)-ureido]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.70-1.25 (m, 10H), 1.48-2.24 (m, 9H), 2.27 (s, 3H),2.49-2.54 (m, 4H), 2.65-4.10 (m, 1H), 6.87-6.93 (m, 2H), 6.99 (s, 1H),7.22-7.26 (m, 2H), 8.50 (s, 0.55H), 8.51 (s, 0.45H), 8.94 (s, 0.55H),8.97 (s, 0.45H); ES-MS m/z 560 (M+H).

Example 110

Compound 1105-[3-Butyl-3-(1-{3-[(6-chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-ureidomethyl]-thiophene-2-carboxylicacid methyl ester

To a 0° C. solution of 5-aminomethyl-thiophene-2-carboxylic acid methylester (Rueckle, T. et al.; J. Med. Chem.; 47; 2004; 6921-6934) (65 mg,0.38 mmol) and Et₃N (106 μL, 0.76 mmol) in CH₂Cl₂ was added dropwisephenyl chloroformate (52 μL, 0.42 mmol). The resulting mixture wasstirred at 0° C. for 1 h. Standard aqueous workup and purification bycolumn chromatography on silica gel (49:1, CH₂Cl₂/MeOH) afforded thephenyl carbamate intermediate.

Following general procedure J, the above phenyl carbamate andN-[3-(4-butylamino-piperidin-1-yl)-butyl]-6-chloro-2,4-dimethyl-nicotinamide(prepared following the Scheme outlined in Table 8) afforded COMPOUND110 as a mixture of diastereoisomers. ¹H NMR (CDCl₃) δ 0.83-2.12 (m,15H), 2.32 (s, 3H), 2.52 (s, 3H), 2.55-3.55 (m, 9H), 3.63-3.66 (m, 1H),3.85 (s, 3H), 4.03-3.19 (m, 1H), 4.55-4.58 (m, 2H), 4.81 (m, 1H), 6.91(d, 1H, J=3.9 Hz), 7.02 (s, 1H), 7.63 (d, 1H, J=3.6 Hz), 8.26 (s, 1H);ES-MS m/z 614 (M+Na).

Example 111

Compound 1115-[3-Butyl-3-1-{3-[(6-chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-ureidomethyl]-thiophene-2-carboxylicacid

To a solution of5-[3-butyl-3-(1-{3-[(6-chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-ureidomethyl]-thiophene-2-carboxylicacid methyl ester (COMPOUND 110) (22 mg, 0.04 mmol) in MeOH (1 ml) wasadded an aqueous solution of NaOH [3.75 M] (60 μL, 0.22 mmol). Thereaction mixture was stirred at 50° C. for 1 h and then diluted withwater (3 ml). The solution was adjusted to pH 4-5 with aqueous HCl [6N].The mixture was extracted with chloroform and the organic layer wasdried over sodium sulfate and concentrated in vacuo. The crude acid (6.5mg, 28%) was used without further purification. ¹H NMR (CDCl₃) δ0.80-0.97 (m, 3H), 1.12-1.52 (m, 6H), 1.70-1.92 (m, 3H), 2.17-2.43 (m,3H), 2.26 (s, 3H), 2.44 (s, 3H), 2.71-2.74 (m, 1H), 2.77-3.17 (m, 5H),3.46-3.68 (m, 5H), 4.30-4.34 (m, 1H), 4.46 (d, 1H, J=15.3 Hz), 4.55 (d,1H, J=15.3 Hz), 4.72 (s, 1H), 6.85 (s, 1H), 6.95 (s, 1H), 7.05 (s, 1H),8.56 (s, 1H); ES-MS m/z 578 (M+H).

Examples 112 to 151 were prepared following the scheme illustratedbelow. R¹ is as shown in the individual examples and R²NH₂ is as definedin the table.

TABLE 10

Example R²NH₂ 112 2-aminobenzimidazole 113 O-isobutylhydroxylaminehydrochloride 114 furfurylamine 1152-[1-(toluene-4-sulfonyl)-1H-imidazol-4-yl]- ethylamine (Bridger et al.,US 2004/209921 A1) 116 1,1-dimethylhyrazine 117 1-methoxy-2-ethylamine118 methoxylpropylamine 119 2-aminoimidazole sulfate 120O-(2-methoxy-ethyl)-hydroxylamine 121 2-picolylamine 122 glycine methylester hydrochloride 123 3-methyl-5-amino-isoxazole 1243-amino-5-methyl-isoxazole 125 2-(aminomethyl-1,3-dioxolane) 1265-amino-3-methylisoxazole 127 4-amino-1,2,4-triazole 1283-amino-1,2,4-triazole 129 4-aminomorpholine 130 3-amino-pyrazole 1311-(2-aminoethyl)-2-imidazolidone 132 2-imidazol-1-yl-ethylamine(Bloomfield, G.C. et al., WO 2005/021519 A2) 1335-amino-3-methyl-isothiazole hydrochloride 134 3-amino-5-methyl-pyrazole135 2-amino-N,N-dimethyl-acetamide 136 O-(2-Methoxy-ethyl)-hydroxylamine(Kim. D.-K. et al., J. Med. Chem., vol. 40(15), 1997, 2363-2373) 137C-(1-methyl-1H-imidazol-4-yl)-methylamine 138 O-tert-butylhydroxylaminehydrochloride 139 C-(3-methyl-3H-imidazol-4-yl)-methylamine 1403-amino-4-pyrazolecarbonitrile 141 aminoacetonitrile hydrochloride 142pyrrolidin-1-ylamine hydrochloride 143 acetic hydrazide 144α-amino-γ-butyrolactone hydrobromide 145 L-alanine-methoxy hydrochloride146 5-amino-3,4-dimethyl-isoxazole 147 5-amino-3,4-dimethylisoxazole 148cyclopropylamine 149 3-amino-propionic acid ethyl ester 1504-amino-butyric acid ethyl ester 151 cyclopropylamine

Example 112

Compound 112N—((R)-3-{4-[3-(1H-Benzoimidazol-2-yl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-6-chloro-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 1.20-1.26 (m, 4H), 1.68-1.75 (m, 3H), 2.20-2.28 (m,1H), 2.29 (s, 3H), 2.49 (s, 3H), 2.49-2.56 (m, 1H), 2.78-2.86 (m, 1H),2.93-3.20 (m, 4H), 3.44-3.64 (m, 3H), 4.39-4.47 (m, 2H), 6.96 (s, 1H),7.01 (d, 1H, J=6 Hz), 7.10-7.15 (m, 4H), 7.24-7.29 (m, 4H), 8.00 (br s,1H); ¹³C NMR (CDCl₃) δ 13.24, 19.40, 22.66, 28.02, 29.07, 30.08, 31.89,37.83, 42.30, 45.38, 52.11, 54.01, 59.89, 111.14, 111.69, 118.97,122.11, 122.90, 122.99, 124.90, 125.88, 126.69, 127.56, 130.69, 132.38,140.33, 147.83, 150.62, 155.67, 168.53; ES-MS m/z 594 (M+H). Anal.Calcd. for C₃₀H₃₆N₇O₂SCl·0.9CH₂Cl₂·1.2H₂O: C, 53.62; H, 5.85; N, 14.16.Found: C, 53.84; H, 5.88; N, 14.20.

Example 113

Compound 1132,6-Dichloro-4-isobutoxy-N—{(R)-3-[4-(3-methyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

¹H NMR (CDCl₃) δ 0.88 (d, 6H, J=6 Hz), 0.92-0.97 (m, 1H), 0.98 (d, 3H,J=6 Hz), 1.14-1.26 (m, 1H), 1.47-1.53 (m, 1H), 1.70-1.74 (m, 3H),1.79-1.86 (m, 1H), 2.09-2.24 (m, 1H), 2.33 (s, 3H), 2.52-2.62 (m, 1H),2.72-2.84 (m, 3H), 3.25-3.36 (m, 1H), 3.53 (d, 2H, J=6 Hz), 3.76 (s,2H), 3.77-3.86 (m, 1H), 4.14-4.26 (m, 1H), 6.95 (s, 1H), 7.00 (d, 1H,J=3 Hz), 7.04 (s, 1H), 7.11 (s, 1H), 7.35-7.41 (m, 1H), 8.83 (br s, 1H);ES-MS m/z 570 (M+H).

Example 114

Compound 1142,6-Dichloro-N—{(R)-3-[4-(3-furan-2-ylmethyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-4-methyl-nicotinamide

¹H NMR (CDCl₃) δ 0.92-0.96 (m, 1H), 0.98 (d, 3H, J=6 Hz), 1.07-1.21 (m,1H), 1.47-1.53 (m, 1H), 1.65-1.76 (m, 3H), 2.09-2.22 (m, 1H), 2.34 (s,3H), 2.55-2.61 (m, 1H), 2.71-2.84 (m, 3H), 3.25-3.37 (m, 1H), 3.81 (s,2H), 3.82-3.91 (m, 1H), 4.21-4.29 (m, 1H), 4.31 (d, 2H, J=6 Hz),4.59-4.67 (m, 1H), 6.03 (br s, 1H), 6.26 (br s, 1H), 6.99 (d, 1H, J=3Hz), 7.06 (s, 2H), 7.27 (s, 1H), 7.32-7.36 (m, 1H), 8.96 (br s, 1H);ES-MS m/z 579 (M+H).

Example 115

Compound 1152,6-Dichloro-N—[(R)-3-(4-{3-[2-(1H-imidazol-4-yl)-ethyl]-1-thiophen-3-ylmethyl-ureido}-piperidin-1-yl)-butyl]-4-methyl-nicotinamide

Pale yellow foam. ¹H NMR (CDCl₃) δ 0.92-0.99 (m, 1H), 0.98 (d, 3H, J=6.6Hz), 1.13-1.17 (m, 1H), 1.48-1.78 (m, 4H), 2.12-2.19 (m, 1H), 2.33 (s,3H), 2.51-2.58 (m, 1H), 2.67-2.85 (m, 5H), 3.25-3.33 (m, 1H), 3.44 (q,2H, J=6 Hz), 3.77-3.87 (m, 3H), 4.12-4.20 (m, 1H), 6.65 (s, 1H), 6.94(d, 1H, J=5.1 Hz), 6.98 (br s, 1H), 7.06 (s, 1H), 7.27-7.30 (m, 1H),7.44 (s, 1H), 8.94 (br d, 1H); ¹³C NMR (CDCl₃) δ 13.41, 19.10, 27.24,30.16, 30.31, 30.99, 40.19, 41.61, 43.40, 51.78, 52.38, 60.25, 121.07,124.32, 126.13, 126.70, 132.57, 134.61, 139.56, 146.61, 149.79, 150.85,158.26, 164.07; ES-MS m/z 592 (M+H). Anal. Calcd. forC₂₇H₃₅N₇O₂SCl₂·1.0CH₂Cl₂·0.4H₂O: C, 49.12; H, 5.56; N, 14.32. Found: C,49.34; H, 5.58; N, 14.39.

Example 116

Compound 1162,6-Dichloro-N—((R)-3-{4-[3-(2,2-dimethylhydrazine-1-ylcarbonylamino)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.91-1.01 (m, 4H), 1.04-1.21 (m, 1H),1.51-1.89 (m, 6H), 2.14-2.21 (m, 1H), 2.34 (s, 3H), 2.40 (s, 6H),2.51-2.59 (m, 1H), 2.68-2.94 (m, 3H), 3.25-3.41 (m, 3H), 3.75-3.88 (m,3H), 4.20-4.41 (m, 1H), 5.00 (s, 1H), 7.01 (d, 1H, J=3 Hz), 7.06 (s,1H), 7.11 (s, 1H), 7.37 (m, 1H), 8.96 (br s, 1H); ES-MS m/z 541 (M+H).

Example 117

Compound 1172,6-Dichloro-N—((R)-3-{4-[3-(2-methoxy-ethyl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.92-0.96 (m, 1H), 0.95 (d, 3H, J=12 Hz),1.06-1.23 (m, 1H), 1.47-1.54 (m, 1H), 1.59-1.75 (m, 5H), 2.17 (t, 1H,J=12 Hz), 2.33 (s, 3H), 2.57 (t, 1H, J=12 Hz), 2.73-2.84 (m, 3H), 3.20(s, 3H), 3.31 (s, 5H), 3.80-3.92 (m, 3H), 4.24 (m, 1H), 6.99 (d, 1H, J=3Hz), 7.01 (s, 3H), 7.11 (s, 1H), 7.34 (m, 1H), 8.96 (br s, 1H); ES-MSm/z 556 (M+H).

Example 118

Compound 1182,6-Dichloro-N—((R)-3-{4-[3-(3-methoxy-propyl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

¹H NMR (CDCl₃) δ 0.82-0.94 (m, 1H), 0.98 (d, 3H, J=6 Hz), 1.04-1.18 (m,1H), 1.49-1.56 (m, 1H), 1.61-1.89 (m, 4H), 2.08-2.19 (m, 1H), 2.34 (s,3H), 2.52-2.61 (m, 1H), 2.72-2.86 (m, 3H), 3.12 (s, 3H), 3.21-3.32 (m,5H), 3.46 (t, 1H, J=6 Hz), 3.79 (s, 2H), 3.80-3.87 (m, 1H), 4.21-4.27(m, 1H), 4.88 (br s, 1H), 7.02 (d, 1H, J=6 Hz), 7.08 (s, 2H), 7.31-7.36(m, 1H), 8.97 (br s, 1H); ES-MS m/z 592 (M+Na).

Example 119

Compound 1192,6-Dichloro-N—((R)-3-{4-[3-(1H-imidazol-2-yl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.98 (d, 3H, J=6.6 Hz), 1.08-1.12 (m, 1H),1.26-1.31 (m, 1H), 1.51-1.56 (m, 1H), 1.68-1.78 (m, 4H), 2.09-2.16 (m,1H), 2.36 (s, 3H), 2.54-2.61 (m, 1H), 2.73-2.86 (m, 3H), 3.28-3.35 (m,1H), 3.78-3.83 (m, 1H), 4.02-4.09 (m, 3H), 6.66 (s, 2H), 6.97 (d, 1H,J=4.8 Hz), 7.10 (s, 2H), 7.33 (dd, 1H, J=4.8, 3 Hz), 8.62 (br d, 1H, J=6Hz); ¹³C NMR (CDCl₃) δ 13.81, 19.58, 30.52, 30.89, 31.32, 40.53, 42.15,43.71, 52.04, 53.75, 60.54, 119.37, 121.67, 124.80, 126.57, 127.21,132.89, 139.29, 144.43, 147.06, 150.43, 151.31, 156.02, 164.53; ES-MSm/z 564 (M+H). Anal. Calcd. for C₂₅H₃₁N₇O₂SCl₂·0.9CH₂Cl₂·0.2H₂O: C,48.26; H, 5.19; N, 15.21. Found: C, 48.28; H, 5.13; N, 15.02.

Example 120

Compound 1202,6-Dichloro-N—{(R)-3-[4-(3-(2-methoxyethoxy)-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-4-methyl-nicotinamide

To a solution of N-hydroxyphthalimide (4.60 g, 28.2 mmol) in DMF (15 ml)was added Et₃N (8.0 ml, 57.4 mmol) followed by 2-bromoethyl methyl ether(4.0 ml, 42.6 mmol) and the reaction stirred for 2.5 days. The mixturewas diluted with EtOAc (50 ml) and brine (50 ml) and the aqueous layerwas extracted with EtOAc (2×15 ml). The combined organic extracts werewashed with brine (4×30 ml), dried (Na₂SO₄) and concentrated to affordthe desired phthalimide as a beige solid (5.52 g, 88%). To a suspensionof the phthalimide (2.13 g, 9.64 mmol) in MeOH (57 ml) was addedhydrazine hydrate (0.4 ml, 12.86 mmol) and the mixture heated to refluxfor 4 h then cooled to rt and stirred overnight. The reaction wasfiltered, concentrated and diluted with Et₂O (30 ml). The Et₂O layer wasfiltered and concentrated and re-diluted with Et₂O (30 ml). The Et₂O wasfiltered again and concentrated to affordO-(2-methoxy-ethyl)-hydroxylamine (775 mg, 88%) as a pale yellow oil. ¹HNMR (CDCl₃) δ 3.38 (s, 3H), 3.55-3.58 (m, 2H), 3.81-3.84 (m, 2H), 4.25(br s, 2H).

COMPOUND 120 was isolated as a yellow foam. ¹H NMR (CDCl₃) δ 0.98 (d,3H, J=6.6 Hz), 1.16-1.24 (m, 1H), 1.48-1.55 (m, 1H), 1.68-1.79 (m, 4H),2.12-2.20 (m, 1H), 2.32 (s, 3H), 2.52-2.59 (m, 1H), 2.72-2.86 (m, 3H),3.25-3.33 (m, 1H), 3.29 (s, 3H), 3.51-3.54 (m, 2H), 3.78-3.84 (m, 3H),3.93-3.97 (m, 2H), 4.14-4.20 (m, 1H), 6.99 (d, 1H, J=4.8 Hz), 7.04 (s,1H), 7.08-7.10 (m, 1H), 7.29 (s, 1H), 7.35 (dd, 1H, J=4.8, 3 Hz), 8.78(br d, 1H, J=6 Hz); ¹³C NMR (CDCl₃) δ 13.33, 19.00, 29.77, 30.40, 30.51,39.91, 41.00, 43.27, 51.46, 52.50, 58.80, 59.92, 70.74, 74.71, 121.21,124.20, 125.88, 127.22, 132.44, 138.65, 146.48, 149.67, 150.76, 158.90,163.98; ES-MS m/z 594 (M+Na). Anal. Calcd. for C₂₅H₃₅N₅O₄SCl₂·0.4H₂O: C,51.79; H, 6.22; N, 12.08. Found: C, 51.89; H, 6.09; N, 12.46.

Example 121

Compound 1212,6-Dichloro-4-methyl-N—{(R)-3-[4-(3-pyridin-2-ylmethyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

¹H NMR (CDCl₃) δ 0.91-0.95 (m, 1H), 0.98 (d, 3H, J=6 Hz), 1.07-1.20 (m,1H), 1.49-1.56 (m, 1H), 1.69-1.78 (m, 3H), 2.09-2.22 (m, 1H), 2.34 (s,3H), 2.53-2.60 (m, 1H), 2.71-2.83 (m, 3H), 3.24-3.35 (m, 1H), 3.80-3.89(m, 1H), 3.89 (s, 2H), 4.21-4.27 (m, 1H), 4.44 (d, 2H, J=3 Hz), 5.57 (m,1H), 7.01-7.05 (m, 2H), 7.09-7.18 (m, 3H), 7.30-7.36 (m, 1H), 7.56-7.61(m, 1H), 8.41 (d, 1H, J=6 Hz), 8.96 (br s, 1H); ES-MS m/z 590 (M+H).

Example 122

Compound 122[3-(1-{(R)-3-[(2,6-Dichloro-4-methyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-3-thiophen-3-ylmethyl-ureido]-aceticacid methyl ester

¹H NMR (CDCl₃) δ 0.95-0.98 (m, 1H), 0.98 (d, 3H, J=6 Hz), 1.08-1.22 (m,1H), 1.48-1.54 (m, 1H), 1.66-1.87 (m, 3H), 2.08-2.20 (m, 1H), 2.34 (s,3H), 2.52-2.58 (m, 1H), 2.71-2.82 (m, 3H), 3.23-3.34 (m, 1H), 3.70 (s,3H), 3.78-3.96 (m, 5H), 4.09-4.23 (m, 1H), 4.84-4.91 (m, 1H), 7.04-7.09(m, 2H), 7.22 (s, 1H), 7.34-7.39 (m, 1H), 8.88 (br s, 1H); ES-MS m/z 570(M+H).

Example 123

Compound 1232,6-Dichloro-4-methyl-N—((R)-3-{4-[3-(3-methyl-isoxazol-5-yl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-nicotinamide

¹H NMR (CDCl₃) δ 1.00 (d+m, 4H), 1.25 (m, 1H), 1.56 (m, 1H), 1.76 (m,3H), 2.20 (s+br t, 4H), 2.35 (s, 3H), 2.61 (br t, 1H), 2.77-2.90 (m,3H), 3.32 (m, 1H), 3.80 (m, 1H), 3.99 (s, 2H), 4.23 (m, 1H), 7.04 (d,1H, J=6.0 Hz), 7.07 (s, 1H), 7.12 (s, 1H), 7.21 (s, 1H), 7.43 (m, 1H),8.64 (br d, 1H); ES-MS m/z 579 (M+H).

Example 124

Compound 1242,6-Dichloro-4-methyl-N—((R)-3-{4-[3-(5-methyl-isoxazol-3-yl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-nicotinamide

¹H NMR (CDCl₃) δ 1.00 (d+m, 4H), 1.24 (m, 1H), 1.56 (m, 1H), 1.76 (m,3H), 2.17 (br t, 1H), 2.35 (s, 6H), 2.60 (br t, 1H), 2.75-2.88 (m, 3H),3.32 (m, 1H), 3.80 (m, 1H), 3.99 (s, 2H), 4.20 (m, 1H), 6.54 (s, 1H),6.97 (s, 1H), 7.04 (d, 1H, J=6.0 Hz), 7.09 (s, 1H), 7.17 (s, 1H), 7.39(m, 1H), 8.69 (br d, 1H); ES-MS m/z 579 (M+H).

Example 125

Compound 1252,6-Dichloro-N—{(R)-3-[4-(3-1,3-dioxolan-2-ylmethyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-4-methyl-nicotinamide

¹H NMR (CDCl₃) δ 0.95-0.99 (m, 4H), 1.05-1.25 (m, 1H), 1.54 (m, 1H),1.68-1.73 (m, 3H), 2.15 (m, 1H), 2.34 (s, 3H), 2.56-2.56 (m, 1H),2.82-2.86 (m, 3H), 3.38-3.42 (m, 3H), 3.74-3.88 (m, 7H), 4.26 (m, 1H),4.56-4.59 (m, 1H), 4.83-5.29 (m, 1H), 7.01-7.05 (m, 2H), 7.13-7.13 (m,1H), 7.33-7.35 (m, 1H), 8.98 (br s, 1H); ES-MS m/z 584(M+H).

Example 126

Compound 1266-Chloro-2,4-dimethyl-N—((R)-3-{4-[3-(3-methyl-isoxazol-5-yl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-nicotinamide

White solid. ¹H NMR (CDCl₃) δ 0.88-1.21 (m, 4H), 1.52-1.74 (m, 5H), 2.21(s, 3H), 2.29 (s, 3H), 2.50 (s, 3H), 2.52-2.70 (m, 1H), 2.71-2.96 (m,3H), 3.22-3.31 (m, 2H), 3.76-3.83 (m, 3H), 4.11-4.24 (m, 1H), 5.97 (s,1H), 6.96 (s, 1H), 7.07-7.10 (m, 1H), 7.21 (s, 1H), 7.42-7.43 (m, 1H),8.57 (br s, 1H); ES-MS m/z 559 (M+H).

Example 127

Compound 1272,6-Dichloro-4-methyl-N—{(R)-3-[4-(1-thiophen-3-ylmethyl-3-[1,2,4]triazol-4-yl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

¹H NMR (CDCl₃) δ 1.00 (br d, 3H), 1.25-1.47 (m, 2H), 1.55 (m, 1H), 1.78(m, 3H), 2.19 (brt, 1H), 2.34 (s, 3H), 2.55 (brt, 1H), 3.33 (m, 1H),3.73 (m, 1H), 4.13 (m, 3H), 7.02 (d, 1H, J=6.0 Hz), 7.08 (s, 1H), 7.18(s, 1H), 7.36 (m, 1H), 7.96 (s, 2H), 8.51 (br s, 1H); ES-MS m/z 565(M+H).

Example 128

Compound 1282,6-Dichloro-4-methyl-N—((R)-3-{4-[1-thiophen-3-ylmethyl-3-(1H-[1,2,4]triazol-3-yl)-ureido]-piperidin-1-yl}-butyl)-nicotinamide

¹H NMR (CDCl₃) δ 0.97 (d+m, 4H), 1.11 (m, 1H), 1.33 (m, 1H), 1.55 (m,1H), 1.77 (m, 3H), 2.20 (br t, 1H), 2.36 (s, 3H), 2.60 (br t, 1H),2.77-2.91 (m, 3H), 3.32 (m, 1H), 3.82 (m, 1H), 4.05 (s, 2H), 4.17 (m,3H), 7.03 (d, 1H, J=6.0 Hz), 7.11 (s, 1H), 7.17 (s, 1H), 7.40 (m, 1H),7.56 (s, 1H), 7.78 (br s, 1H), 8.57 (br s, 1H); ES-MS m/z 565 (M+H).

Example 129

Compound 1292,6-Dichloro-4-methyl-N—{(R)-3-[4-(3-morpholin-4-yl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

¹H NMR (CDCl₃) δ 0.94 (d+m, 4H), 1.12 (m, 1H), 1.54 (m, 1H), 1.73 (m,3H), 2.20 (br t, 1H), 2.34 (s, 3H), 2.59 (m, 5H), 2.76-2.86 (m, 3H),3.32 (m, 1H), 3.47 (s, 1H), 3.69 (m, 4H), 3.83 (s+m, 3H), 4.24 (m, 1H),7.00 (d, 1H, J=6.0 Hz), 7.05 (s, 1H), 7.11 (s, 1H), 7.38 (m, 1H), 8.84(br s, 1H); ES-MS m/z 583 (M+H).

Example 130

Compound 1302,6-Dichloro-4-methyl-N—((R)-3-{4-[3-(1H-pyrazol-3-yl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-nicotinamide

¹H NMR (CDCl₃) δ 0.97 (d+m, 4H), 1.22 (m, 1H), 1.54 (m, 1H), 1.75 (m,3H), 2.20 (brt, 1H), 2.35 (s, 3H), 2.59 (m, 5H), 2.76-2.86 (m, 3H), 3.34(m, 1H), 3.82 (m, 1H), 3.98 (s, 2H), 4.27 (m, 1H), 6.36 (br s, 1H), 6.91(s, 1H), 7.06 (m, 1H), 7.09 (s, 1H), 7.21 (s, 1H), 7.39 (s+m, 1H), 8.79(br s, 1H); ES-MS m/z 564 (M+H).

Example 131

Compound 1312,6-Dichloro-4-methyl-N—[(R)-3-(4-{3-[2-(2-oxo-imidazolidin-1-yl)-ethyl]-1-thiophen-3-ylmethyl-ureido}-piperidin-1-yl)-butyl]-nicotinamide

¹H NMR (CDCl₃) δ 0.98 (d+m, 4H), 1.16 (m, 1H), 1.24 (m, 2H), 1.55 (m,1H), 1.66-1.76 (m, 3H), 2.08 (br t, 1H), 2.33 (s, 3H), 2.58 (m, 2H),2.65 (m, 1H), 2.83 (m, 2H), 3.21 (m, 2H), 3.31 (m, 3H), 3.78 (m, 1H),3.85 (s, 2H), 4.07 (m, 1H), 4.86 (br t, 1H), 6.98 (d, 1H, J=6.0 Hz),7.05 (s, 1H), 7.08 (s, 1H), 7.11 (s, 1H), 7.31 (m, 1H), 7.66 (s, 1H),8.82 (br s, 1H); ES-MS m/z 586 (M+H).

Example 132

Compound 1322,6-Dichloro-N—((R)-3-{4-[3-(2-imidazol-1-vl-ethyl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

¹H NMR (CDCl₃) δ 0.92-0.99 (m, 1H), 0.98 (d, 3H, J=6.6 Hz), 1.13-1.26(m, 1H), 1.48-1.78 (m, 5H), 2.13-2.20 (m, 1H), 2.33 (s, 3H), 2.52-2.60(m, 10H), 2.73-2.87 (m, 3H), 3.26-3.33 (m, 1H), 3.39-3.46 (m, 2H), 3.75(s, 2H), 3.77-3.86 (m, 1H), 4.00 (t, 1H, J=5.7 Hz), 4.10-4.22 (m, 1H),4.38-4.46 (m, 1H), 6.72 (s, 1H), 6.92 (d, 1H, J=4.8 Hz), 6.97 (br s,1H), 7.00 (s, 1H), 7.06 (s, 1H), 7.29 (s, 1H), 7.35 (dd, 1H, J=4.8, 3Hz), 8.82 (br d, 1H); ¹³C NMR (CDCl₃) δ 13.79, 19.52, 30.52, 30.84,31.32, 40.52, 42.07, 43.77, 47.06, 52.17, 52.80, 60.62, 119.04, 121.61,124.71, 126.28, 127.84, 130.07, 132.99, 137.53, 139.47, 147.04, 150.19,151.28, 158.24, 164.45; ES-MS m/z 614 (M+Na). Anal. Calcd. forC₂₇H₃₅N₇O₂SCl₂·0.6CH₂Cl₂·0.6H₂O: C, 50.66; H, 5.76; N, 14.98. Found: C,50.70; H, 5.77; N, 15.01.

Example 133

Compound 1332,6-Dichloro-4-methyl-N—((R)-3-{4-[3-(3-methyl-isothiazol-5-yl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-nicotinamide

¹H NMR (CDCl₃) δ 1.00 (d+m, 4H), 1.25 (m, 1H), 1.53 (m, 1H), 1.76 (m,3H), 2.20 (br t, 1H), 2.30 (s, 3H), 2.37 (s, 3H), 2.58 (br t, 1H),2.81-2.87 (m, 3H), 3.32 (m, 1H), 3.76 (m, 1H), 4.02 (s, 2H), 4.32 (m,1H), 7.05 (d, 1H, J=6.0 Hz), 7.07 (s, 1H), 7.23 (s, 1H), 7.43 (m, 1H),7.48 (s, 1H), 8.71 (br s, 1H); ES-MS m/z 596 (M+H).

Example 134

Compound 1342,6-Dichloro-4-methyl-N—((R)-3-{4-[3-(5-methyl-1H-pyrazol-3-yl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-nicotinamide

¹H NMR (CDCl₃) δ 1.00 (d+m, 4H), 1.24 (m, 1H), 1.52 (m, 1H), 1.74 (m,3H), 2.23 (s+brt, 4H), 2.35 (s, 3H), 2.58 (brt, 1H), 2.74-2.85 (m, 3H),3.31 (m, 1H), 3.73 (m, 1H), 3.96 (s, 2H), 4.25 (m, 1H), 6.82 (s, 1H),7.05 (d, 1H, J=6.0 Hz), 7.09 (s, 1H), 7.19 (s, 1H), 7.38 (m, 1H), 8.81(br s, 1H); ES-MS m/z 578 (M+H).

Example 135

Compound 1352,6-Dichloro-N—{(R)-3-[4-(3-dimethylcarbamoylmethyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-4-methyl-nicotinamide

¹H NMR (CDCl₃) δ 0.98 (d, 3H, J=6 Hz), 0.98-1.07 (m, 1H), 1.09-1.22 (m,1H), 1.47-1.51 (m, 1H), 1.70-1.79 (m, 3H), 2.07-2.20 (m, 1H), 2.34 (s,3H), 2.54-2.62 (m, 1H), 2.73-2.88 (m, 3H), 2.94 (s, 6H), 3.26-3.35 (m,1H), 3.75-3.80 (m, 1H), 3.81 (s, 2H), 3.96 (d, 2H, J=6 Hz), 4.01-4.16(m, 1H), 5.44-5.49 (m, 1H), 7.01-7.06 (m, 2H), 7.20 (s, 1H), 7.28-7.35(m, 1H), 8.86 (br s, 1H); ES-MS m/z 583 (M+H).

Example 136

Compound 1366-Chloro-N—((R)-3-{4-[3-(2-methoxyethoxy)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.83-0.94 (m, 1H), 0.98 (d, 3H, J=6.6 Hz), 0.98-1.07(m, 1H), 1.48-1.54 (m, 1H), 1.63-1.76 (m, 3H), 2.13-2.20 (m, 1H), 2.27(s, 3H), 2.48 (s, 3H), 2.53-2.60 (m, 1H), 2.68-2.84 (m, 3H), 3.22-3.31(m, 1H), 3.29 (s, 3H), 3.52-3.55 (m, 2H), 3.65-3.75 (m, 2H), 3.81-3.87(m, 1H), 3.94-3.97 (m, 2H), 4.16-4.24 (m, 1H), 6.93 (s, 1H), 7.03 (d,1H, J=4.8 Hz), 7.10 (br s, 1H), 7.28 (s, 1H), 7.37 (dd, 1H, J=4.8, 3Hz), 8.76 (br d, 1H); ¹³C NMR (CDCl₃) δ 15.31, 20.57, 23.87, 31.52,32.42, 41.89, 42.76, 45.12, 53.53, 54.14, 60.76, 62.25, 72.69, 76.68,123.10, 124.26, 127.84, 129.17, 134.67, 140.61, 149.36, 151.85, 157.17,160.83, 168.84; ES-MS m/z 574 (M+Na). Anal. Calcd. forC₂₆H₃₈N₅O₄SCl·0.3CH₂Cl₂·0.2H₂O: C, 54.35; H, 6.76; N, 12.05. Found: C,54.35; H, 6.74; N, 12.07.

Example 137

Compound 1372,6-Dichloro-4-methyl-N—((R)-3-{4-[3-(1-methyl-1H-imidazol-4-ylmethyl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-nicotinamide

¹H NMR (CDCl₃) δ 0.93-0.96 (m, 1H), 0.98 (d, 3H, J=6 Hz), 1.04-1.19 (m,1H), 1.46-1.53 (m, 1H), 1.66-1.78 (m, 4H), 2.07-2.20 (m, 1H), 2.34 (s,3H), 2.54-2.60 (m, 1H), 2.71-2.83 (m, 3H), 3.24-3.38 (m, 1H), 3.60 (s,3H), 3.83 (br s, 3H), 4.20-4.29 (m, 3H), 4.82-4.87 (m, 1H), 6.62 (s,1H), 6.97-7.00 (m, 1H), 7.06-7.08 (m, 2H), 7.27-7.33 (m, 1H), 8.91 (brs, 1H); ES-MS m/z 592 (M+H).

Example 138

Compound 1386-Chloro-N—{(R)-3-[4-(3-t-butoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.78-0.93 (m, 1H), 0.98 (d, 3H, J=6 Hz), 098-1.02 (m,1H), 1.14 (s, 9H), 1.48-1.55 (m, 1H), 1.63-1.77 (m, 3H), 2.15-2.22 (m,1H), 2.27 (s, 3H), 2.49 (s, 3H), 2.52-2.59 (m, 1H), 2.68-2.86 (m, 3H),3.21-3.30 (m, 1H), 3.71 (s, 2H), 3.77-3.91 (m, 1H), 4.19-4.28 (m, 1H),6.57 (s, 1H), 6.90 (s, 1H), 7.01-7.05 (m, 1H), 7.13 (s, 1H), 7.35-7.40(m, 1H), 8.82 (br s, 1H); ES-MS m/z 572 (M+Na).

Example 139

Compound 1392,6-Dichloro-4-methyl-N—((R)-3-{4-[3-(3-methyl-3H-imidazol-4-ylmethyl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-nicotinamide

¹H NMR (CDCl₃) δ 0.93-0.98 (m, 1H), 0.98 (d, 3H, J=6 Hz), 1.09-1.19 (m,1H), 1.48-1.54 (m, 1H), 1.68-1.79 (m, 3H), 2.08-2.20 (m, 1H), 2.33 (s,3H), 2.56-2.62 (m, 1H), 2.70-2.84 (m, 3H), 3.23-3.38 (m, 1H), 3.45 (s,3H), 3.83 (s, 2H), 3.83-3.91 (m, 1H), 4.19-4.26 (m, 1H), 4.28 (d, 2H,J=6 Hz), 4.40-4.47 (m, 1H), 6.73 (br s, 1H), 6.94-6.98 (m, 1H), 7.04 (s,2H), 7.32-7.36 (m, 2H), 8.88 (br s, 1H); ES-MS m/z 592 (M+H).

Example 140

Compound 1402,6-Dichloro-N—((R)-3-{4-[3-(4-cyano-1H-pyrazol-3-yl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

¹H NMR (CDCl₃) δ 1.01 (d, 3H, J=6.0 Hz), 1.25 (m, 1H), 1.43 (s, 1H),1.56 (m, 1H), 1.82 (m, 3H), 2.26 (br t, 1H), 2.35 (s, 3H), 2.67 (br t,1H), 2.88-2.95 (m, 3H), 3.34 (m, 1H), 3.81 (m, 1H), 4.02 (s, 2H), 4.27(m, 1H), 7.01 (s+d, 2H), 7.32 (s, 1H), 7.38 (s, 1H), 7.49 (m, 1H), 7.55(s, 1H), 8.57 (br s, 1H); ES-MS m/z 589 (M+H).

Example 141

Compound 1412,6-Dichloro-N—{(R)-3-[4-(3-cyanomethyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-4-methyl-nicotinamide

¹H NMR (CDCl₃) δ 0.99 (d+m, 4H), 1.23 (m, 1H), 1.50-1.77 (m, 4H), 2.14(br t, 1H), 2.35 (s, 3H), 2.56 (br t, 1H), 2.73-2.84 (m, 3H), 3.29 (m,1H), 3.84 (s+m, 3H), 4.03 (d, 2H, J=6.0 Hz), 4.21 (m, 1H), 4.62 (m, 1H),7.02 (d, 2H, J=4.5 Hz), 7.13 (s+d, 2H), 7.41 (m, 1H), 8.80 (br s, 1H);ES-MS m/z 537 (M+H).

Example 142

Compound 1426-Chloro-2,4-dimethyl-N—{(R)-3-[4-(3-pyrrolidin-1-yl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

¹H NMR (CDCl₃) δ 0.72-0.84 (m, 1H), 0.97 (d, 3H, J=6 Hz), 098-1.03 (m,1H), 1.46-1.52 (m, 1H), 1.62-1.78 (m, 7H), 2.14-2.21 (m, 1H), 2.27 (s,3H), 2.48 (s, 3H), 2.50-2.55 (m, 1H), 2.57-2.69 (m, 5H), 2.77-2.86 (m,2H), 3.21-3.27 (m, 1H), 3.68 (d, 2H, J=6 Hz), 3.78-3.92 (m, 1H),4.21-4.29 (m, 1H), 5.01 (s, 1H), 6.93 (s, 1H), 7.02-7.06 (m, 1H), 7.11(s, 1H), 7.33-7.38 (m, 1H), 8.91 (br s, 1H); ES-MS m/z 569 (M+Na).

Example 143

Compound 1432,6-Dichloro-4-methyl-N—{(R)-3-[4-(3-acetamido-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

¹H NMR (CDCl₃) δ 0.99 (d, 3H, J=6.0 Hz), 1.12 (m, 1H), 1.23 (m, 1H),1.54 (m, 1H), 1.69-1.79 (m, 4H), 1.98 (s, 3H), 2.16 (br t, 1H), 2.34 (s,3H), 2.57 (br t, 1H), 2.76 (m, 1H), 2.86 (m, 2H), 3.31 (m, 1H), 3.80 (m,1H), 3.99 (s, 2H), 4.09 (m, 1H), 6.59 (br s, 1H), 7.06 (d, 1H, J=6.0Hz), 7.11 (s, 1H), 7.28 (s, 1H), 7.37 (m, 1H), 7.75 (s, 1H), 8.65 (br s,1H); ES-MS m/z 555 (M+H).

Example 144

Compound 1442,6-Dichloro-4-methyl-N—((R)-3-{4-[3-(2-oxo-tetrahydro-furan-3-yl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-nicotinamide

¹H NMR (CDCl₃) δ 0.98 (d+m, 4H), 1.25 (m, 1H), 1.57 (m, 1H), 1.69-1.77(m, 4H), 2.08-2.17 (m, 2H), 2.35 (s, 3H), 2.56 (br t, 1H), 2.63-2.88 (m,4H), 3.27 (m, 1H), 3.88 (s+m, 3H), 4.20 (m, 2H), 4.33 (m, 2H), 4.87 (m,1H), 7.02 (d, 1H, J=6.0 Hz), 7.08 (s, 1H), 7.17 (s, 1H), 7.37 (m, 1H),8.82 (br s, 1H); ES-MS m/z 582 (M+H).

Example 145

Compound 145(S)-2-[3-(1-{(R)-3-[(2,6-Dichloro-4-methyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-3-thiophen-3-ylmethyl-ureido]-propionicacid methyl ester

¹H NMR (CDCl₃) δ 0.92 (d+m, 4H), 1.17 (m, 1H), 1.25 (d, 1H, J=6.0 Hz),1.57 (m, 1H), 1.64-1.75 (m, 4H), 2.16 (br t, 1H), 2.35 (s, 3H), 2.53 (brt, 1H), 2.71 (m, 1H), 2.84 (m, 2H), 3.28 (m, 1H), 3.69 (s, 3H),3.75-3.85 (m, 2H), 4.18 (m, 1H), 4.39 (m, 1H), 4.80 (d, 1H, J=6.0 Hz),7.07 (m, 2H), 7.21 (s, 1H), 7.36 (m, 1H), 8.87 (br s, 1H); ES-MS m/z 584(M+H).

Example 146

Compound 1466-Chloro-N—((R)-3-{4-[3-(3,4-dimethyl-isoxazol-5-yl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.95 (d+m, 4H), 1.12 (m, 1H), 1.53 (m, 1H), 1.75 (s+m,6H), 2.14 (s, 3H), 2.18 (br t, 1H), 2.29 (s, 3H), 2.50 (s, 3H), 2.60 (brt, 1H), 2.73 (m, 1H), 2.83 (m, 2H), 3.28 (br t, 1H), 3.83 (m, 1H), 3.90(s, 2H), 4.25 (m, 1H), 6.33 (s, 1H), 6.97 (s, 1H), 7.10 (d, 1H, J=6.0Hz), 7.23 (s, 1H), 7.43 (m, 1H), 8.73 (br s, 1H); ES-MS m/z 573 (M+H).

Example 147

Compound 1476-Cyano-N—((R)-3-{4-[3-(3,4-dimethyl-isoxazol-5-yl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.95 (d+m, 4H), 1.10 (m, 1H), 1.53 (m, 1H), 1.73 (s+m,6H), 2.14 (s, 3H), 2.17 (br t, 1H), 2.35 (s, 3H), 2.56 (s, 3H), 2.59 (brt, 1H), 2.75 (m, 1H), 2.85 (m, 2H), 3.33 (br t, 1H), 3.82 (m, 1H), 3.91(s, 2H), 4.26 (m, 1H), 6.32 (s, 1H), 7.06 (d, 1H, J=6.0 Hz), 7.26 (s,2H), 7.47 (m, 1H), 8.65 (br s, 1H); ES-MS m/z 564 (M+H).

Example 148

Compound 1486-Chloro-N—{(R)-3-[4-(3-cyclopropyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.26-0.29 (m, 2H), 0.58-0.64 (m, 2H), 0.74-1.03 (m,5H), 1.52-1.76 (m, 4H), 2.14 (t, 1H, J=12 Hz), 2.27 (s, 3H), 2.48-2.74(m, 6H), 2.75-2.82 (m, 2H), 3.25 (br t, 1H, J=12 Hz), 3.58-3.70 (m, 2H),3.78-3.91 (m, 1H), 4.23-4.28 (m, 1H), 4.48 (br s, 1H), 6.93 (s, 1H),7.01 (d, 1H, J=6 Hz), 7.08 (br s, 1H), 7.34 (dd, 1H, J=6, 3 Hz), 8.92(br s, 1H); ES-MS m/z 540 (M+Na).

Example 149

Compound 1493-[3-(1-{(R)-3-[(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-3-thiophen-3-ylmethyl-ureido]-propionicacid ethyl ester

¹H NMR (CDCl₃) δ 0.67-2.91 (m, 11H), 0.98 (d, 3H, J=6.6 Hz), 1.18 (t,3H, J=7.2 Hz), 2.26 (s, 3H), 2.40 (t, 2H, J=6.0 Hz), 2.47 (s, 3H),3.25-3.27 (m, 1H), 3.37 (q, 2H, J=6.0 Hz), 3.62-3.91 (m, 3H), 4.02 (q,2H, J=7.2 Hz), 4.12-4.30 (m, 2H), 4.80-4.90 (m, 1H), 6.93 (s, 1H),6.94-7.00 (m, 1H), 7.07 (s, 1H), 7.31-7.33 (m, 1H), 8.81 (s, 1H); ES-MSm/z 578 (M+H).

Example 150

Compound 1504-[3-(1-{(R)-3-[(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-3-thiophen-3-ylmethyl-ureido]-butyricacid ethyl ester

¹H NMR (CDCl₃) δ 0.75-2.89 (m, 11H), 0.97 (d, 3H, J=6.6 Hz), 1.21 (t,3H, J=6.9 Hz), 1.68 (t, 2H, J=7.2 Hz), 2.15 (t, 2H, J=7.2 Hz), 2.26 (s,3H), 2.48 (s, 3H), 3.13 (q, 2H, J=6.3 Hz), 3.20-3.32 (m, 1H), 3.33-3.88(m, 3H), 4.07 (q, 2H, J=7.2 Hz), 4.12-4.27 (m, 1H), 4.41-4.50 (m, 1H),6.94 (s, 1H), 6.95-7.00 (m, 1H), 7.11 (s, 1H), 7.33-7.35 (m, 1H), 8.85(s, 1H); ES-MS m/z 614 (M+Na).

Example 151

Compound 151N—{(R)-3-[4-(3-Cyclopropyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-6-fluoro-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.25 (m, 2H), 0.59 (m, 2H), 0.8 (m, 1H), 1.0 (m, 9H),1.52 (d, 1H, J=12 Hz), 1.65 (m, 5H), 2.15 (t, 1H, J=12 Hz), 2.30 (s,3H), 2.45 (s, 3H), 2.5 (m, 3H), 2.8 (m, 1H), 2.85 (m, 2H), 3.25 (t, 1H,J=12 Hz), 3.61 (s, 2H), 3.85 (m, 1H), 4.26 (m, 1H), 4.44 (s, 1H), 6.43(s, 1H), 6.95 (d, 1H, J=3 Hz), 7.05 (s, 1H), 7.35 (d, 1H, J=3 Hz), 8.85(br d, 1H, J=6 Hz); ES-MS m/z 509 (M+H).

Example 152

Compound 1522,6-Dichloro-4-methyl-N—{(R)-3-[4-(3-cyano-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

To a stirred solution of2,6-dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(128 mg, 0.28 mmol) and DIPEA (98 μL, 0.56 mmol) in CH₂Cl₂ (4 ml) wasadded solid triphosgene (25 mg, 0.084 mmol) in one portion. After 30min, sodium hydrogencyanamide (22 mg, 0.34 mmol) was added and theresulting suspension was stirred overnight. A fine white precipitate wasobserved. The solvent was then removed under reduced pressure, and thecrude material was purified by flash chromatography on silica gel(CH₂Cl₂/CH₃OH/NH₄OH, 10:2:0.5) to give COMPOUND 152 (114 mg, 77%) as awhite solid. ¹H NMR (CD₃OD) δ 1.37 (d, 3H, J=6.6 Hz), 1.80-1.86 (m, 3H),2.07-2.13 (m, 3H), 2.36 (s, 3H), 3.03-3.10 (m, 2H), 3.31-3.53 (m, 4H),4.21 (br s, 1H), 4.47 (br s, 2H), 4.60 (br s, 1H), 7.04 (d, 1H, J=4.5Hz), 7.14 (br s, 1H), 7.31 (dd, 1H, J=5, 3 Hz), 7.41 (s, 1H); ES-MS m/z523 (M+H).

Example 153

Compound 1532,6-Dichloro-4-amino-N—{(R)-3-[4-(3-methyl-1-thiophen-3-ylmethylureido)-piperidin-1-yl]-butyl}-nicotinamide

To a solution of N-aminophthalimide (285 mg, 1.76 mmol) in acetonitrile(4 mL) was added CDI (285 mg, 1.76 mmol) and diisopropylethylamine (310μL, 1.76 mmol). The solution was stirred at 55° C. overnight and thereaction was subjected to aqueous work-up. The crude was immediatelytaken up in a solution of methanol (4 mL) and hydrazine (10 equiv, 78μL) and allowed to stir at room temperature overnight. Solvent wasremoved in vacuo, followed by an aqueous work-up and purification bycolumn chromatography (5% MeOH:DCM) to give COMPOUND 153 (73 mg, 56%) asa white solid. ¹H NMR (CDCl₃) δ 0.98 (d, 3H, J=6 Hz), 0.98-1.01 (m, 1H),1.10-1.22 (m, 1H), 1.47-1.76 (m, 3H), 2.06-2.18 (m, 1H), 2.33 (s, 3H),2.51-2.63 (m, 1H), 2.72-2.83 (m, 3H), 3.22-3.31 (m, 1H), 3.67 (br s,2H), 3.81 (br s, 2H), 3.81-3.90 (m, 1H), 4.04-4.18 (m, 1H), 5.50 (br s,1H), 6.98 (d, 1H, J=3 Hz), 7.04-7.10 (m, 2H), 7.24 (s, 1H), 7.33-7.38(m, 1H), 8.81 (br s, 1H); ES-MS m/z 513 (M+H).

Example 154

Compound 154N—{(R)-3-[4-(3-Carbamoylmethyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-2,6-dichloro-4-methyl-nicotinamide

To a stirred solution of glycine methyl ester hydrochloride (109 mg,0.87 mmol) and DIPEA (275 μL, 1.56 mmol) in CH₂Cl₂ (3 ml) was added CDI(155 mg, 0.96 mmol). The solution was stirred at 40° C. for 2 h before asolution of2,6-dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(130 mg, 0.29 mmol) in CH₂Cl₂ (3 ml) was added. Stirring was continuedovernight at 40° C. Solvent was removed and the crude residue waspurified by flash chromatography (MeOH/CH₂Cl₂, 3-4%) to give the ester(109 mg, 66%).

The above ester (30 mg, 0.05 mmol) was taken up in MeOH (4 ml) and thesolution was saturated with gaseous ammonia. The saturated solution wasallowed to stir at rt overnight. Solvent was removed and COMPOUND 154(28 mg, 97%) was recovered as a white foam. ¹H NMR (CDCl₃) δ 0.98 (d,3H, J=12 Hz), 0.99-1.11 (m, 1H), 1.19-1.27 (m, 1H), 1.51-1.59 (m, 1H),1.68-1.77 (m, 3H), 2.16 (t, 1H, J=12 Hz), 2.33 (s, 3H), 2.55 (t, 1H,J=12 Hz), 2.73-2.89 (m, 3H), 3.28-3.39 (m, 1H), 3.78 (d, 2H, J=3 Hz),3.79-3.82 (m, 1H), 3.90 (s, 2H), 4.09-4.22 (m, 1H), 5.03-5.07 (m, 1H),5.45 (br s, 1H), 6.18 (br s, 1H), 7.01 (d, 1H, J=3 Hz), 7.06 (s, 1H),7.16 (br s, 1H), 7.34 (m, 1H), 8.81 (br s, 1H); ES-MS m/z 555 (M+H).

Example 155

Compound 155[3-(1-{(R)-3-[(2,6-Dichloro-4-methyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-3-thiophen-3-ylmethyl-ureido]-aceticacid

To a solution of glycine t-butyl ester hydrochloride (74 mg, 0.44 mmol)in CH₃CN (5 ml) was added CDI (71 mg, 0.44 mmol), followed by DIPEA(0.077 mL, 0.44 mmol), and the mixture was stirred at 60° C. for 2 h. Asolution of2,6-dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(50 mg, 0.11 mmol) in CH₃CN (5 ml) was then added to the previousmixture. After stirring at 60° C. overnight, the mixture wasconcentrated in vacuo and diluted with CH₂Cl₂ (15 ml) and saturatedNaHCO₃ (20 ml). The aqueous layer was extracted with CH₂Cl₂ (3×10 ml),then the combined organic extracts were dried over Na₂SO₄ andconcentrated. The crude product was purified by flash chromatography(CH₂Cl₂, 5% MeOH, 1% NH₄OH) to afford[3-(1-{(R)-3-[(2,6-dichloro-4-methyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-3-thiophen-3-ylmethyl-ureido]-aceticacid tert-butyl ester as a clear oil (95 mg). ¹H NMR (CDCl₃) δ 0.96-0.98(d, 3H, J=6 Hz), 1.11-1.38 (m, 2H), 1.42 (s, 9H), 1.48-1.57 (m, 1H),1.61-1.79 (m, 3H), 2.10-2.23 (m, 1H), 2.34 (s, 3H), 2.50-2.58 (m, 1H),2.73-2.93 (m, 3H), 3.24-3.38 (m, 1H), 3.81-3.85 (d, 2H, J=12 Hz), 3.89(s, 2H), 4.11-4.23 (m, 1H), 4.76-4.82 (m, 1H), 7.04-7.06 (d, 1H, J=6Hz), 7.09 (s, 1H), 7.20 (s, 1H), 7.33-7.35 (d, 1H, J=6 Hz), 7.66 (br s,1H), 8.90 (br s, 1H).

To a solution of the above ester (0.11 mmol) in CH₂Cl₂ (3 ml), was addedTFA (1 ml). The mixture was stirred at rt for 2 h, concentrated, thendiluted with CH₂Cl₂ (20 ml) and H₂O (5 ml). The pH of the aqueous layerwas adjusted to 5 with 1N NaOH and the product was extracted with CH₂Cl₂(3×8 ml). The organic extracts were dried with Na₂SO₄ and concentrated.Due to low crude recovery, the aqueous layer and organic extracts werecombined, concentrated in vacuo, and dry-loaded onto a column. The crudeproduct was purified with 8:1:1 CH₃CN/MeOH/NH₄OH to give COMPOUND 155(48 mg, 78% yield) as a white solid. ¹H NMR (CDCl₃ with some CD₃OD): δ1.11-1.13 (d, 3H, J=6 Hz), 1.50-1.91 (m, 4H), 2.22 (s, 3H), 2.50-2.63(m, 1H), 2.72-2.81 (m, 1H), 2.96-3.17 (m, 3H), 3.22-3.48 (m, 2H), 3.60(s, 2H), 3.67-3.77 (m, 3H), 4.02-4.12 (m, 1H), 4.16 (s, 2H), 6.84-6.86(d, 1H, J=6 Hz), 7.03 (s, 1H), 7.06 (s, 1H), 7.17-7.18 (d, 1H, J=3 Hz).¹³C NMR (CDCl₃ with some CD₃OD): δ 12.55, 18.89, 27.42, 27.76, 30.85,36.83, 42.16, 44.35, 45.26, 48.06, 48.35, 48.63, 48.92, 49.20, 49.49,49.77, 50.29, 50.99, 58.77, 121.39, 124.43, 126.23, 126.71, 131.88,139.41, 146.41, 149.93, 150.81, 158.11, 165.48, 175.15. ES-MS m/z 556(M+H).

Example 156

Compound 1562,6-Dichloro-N-(3-{4-[3-(2-hydroxy-ethyl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

To an ice cold solution of ethanolamine (9.27 ml, 154 mmol) indichloromethane (15 ml) was added t-butyldiphenylsilyl chloride (4 ml,15.4 mmol); the solution was allowed to stir at room temperatureovernight. Following aqueous work up the crude2-(tert-butyl-diphenyl-silanyloxy)-ethylamine was recovered as acolorless oil (4.53 g, 98%) and used as is in the next step. ¹H NMR(CDCl₃) δ 1.06 (s, 9H), 1.61 (br s, 2H), 2.79 (t, 2H, J=6 Hz), 3.66 (t,2H, J=6 Hz), 7.35-7.46 (m, 6H), 7.65-7.73 (m, 4H).

Using general procedure I,[2-(tert-butyl-diphenyl-silanyloxy)-ethylamine] and2,6-dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamidegave the desired urea. The resulting urea was taken up in methanol (25ml) and concentrated HCl (0.5 ml). The resulting solution was allowed tostir at room temperature overnight. The solvent was removed and theresidue was taken up in dichloromethane and washed with 1M NaOH, theorganic layer was dried over Na₂SO₄. The crude was purified by columnchromatography on silica gel (4% MeOH/DCM) to give COMPOUND 156 as awhite solid (109 mg, 94%). ¹H NMR (CDCl₃) δ 0.91-1.07 (m, 4H), 1.09-1.24(m, 1H), 1.50-1.57 (m, 1H), 1.69-1.87 (m, 3H), 2.08-2.19 (m, 1H), 2.34(s, 3H), 2.52-2.57 (m, 1H), 2.71-2.80 (m, 3H), 3.23-3.34 (m, 4H),3.52-3.58 (m, 2H), 3.76-3.79 (m, 1H), 3.85 (s, 2H), 4.11-4.19 (m, 1H),4.87-4.94 (m, 1H), 7.01 (d, 1H, J=3 Hz), 7.08 (s, 1H), 7.12 (s, 1H),7.33-7.38 (m, 1H), 8.90 (br s, 1H); ES-MS m/z 542 (M+H).

Examples 157 to 165 were prepared following the scheme below whereinR¹NCO is defined in the table and R² is as shown in the individualexamples.

Table 11

Example R¹NCO 157* benzyl isocyanate 158* tert-butyl isocyanate 159*phenyl isocyanate 160* Cyclohexyl isocyanate 161 3,5-dimethylisoxazol-4-yl isocyanate 162  pyridine-3-isocyanate 163 ethoxycarbonyl isocyanate 164  methyl isocyanate 165  methyl isocyanate*= racemic

Example 157

Compound 157N-{3-[4-(3-Benzyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-6-chloro-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.81-0.99 (m, 1H), 0.99 (d, 3H, J=9 Hz), 0.99-1.07 (m,1H), 1.69-1.78 (m, 3H), 2.20 (m, 1H), 2.28 (s, 3H), 2.49 (s, 3H),2.52-2.60 (m, 1H), 2.71-2.89 (m, 3H), 3.26 (m, 1H), 3.74 (s, 2H),3.76-3.88 (m, 1H), 4.25-4.36 (m, 1H), 4.30 (d, 2H, J=6 Hz), 4.63 (m,1H), 6.93 (s, 1H), 7.02-7.11 (m, 4H), 7.19-7.27 (m, 4H), 7.32-7.37 (m,1H), 8.96 (s, 1H); ES-MS m/z 569(M+H).

Example 158

Compound 158N-{3-[4-(3-tert-Butyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-6-chloro-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.77-0.93 (m, 1H), 0.98 (d, 3H, J=6 Hz), 098-1.02 (m,1H), 1.16 (s, 9H), 1.51-1.58 (m, 1H), 1.62-1.79 (m, 3H), 2.15 (m, 1H),2.27 (s, 3H), 2.49 (s, 3H), 2.52-2.58 (m, 1H), 2.67-2.87 (m, 3H), 3.26(m, 1H), 3.64 (s, 2H), 3.92 (m, 1H), 4.17 (s, 1H), 4.26 (m, 1H), 6.91(s, 1H), 7.00 (m, 1H), 7.13 (m, 1H), 7.36 (m, 1H), 8.99 (br s, 1H);ES-MS m/z 535 (M+H).

Example 159

Compound 1596-Chloro-2,4-dimethyl-N-{3-[4-(3-phenyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

¹H NMR (CDCl₃) δ 0.81-1.17 (m, 5H), 1.50-1.57 (m, 1H), 1.72-1.78 (m,3H), 2.22-2.27 (m, 1H), 2.30 (s, 3H), 2.51 (s, 3H), 2.52-2.57 (m, 1H),2.63-2.89 (m, 4H), 3.26 (m, 1H), 3.81-3.87 (m, 3H), 4.28 (m, 1H), 6.30(br s, 1H), 6.94-7.02 (m, 2H), 7.11-7.14 (m, 3H), 7.17-7.22 (m, 2H),7.43-7.46 (m, 1H), 8.92 (br s, 1H); ES-MS m/z 554 (M+H).

Example 160

Compound 1606-Chloro-N-{3-[4-(3-cyclohexyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.88-1.12 (m, 8H), 1.19-1.24 (m, 2H), 1.47-1.54 (m,4H), 1.62-1.79 (m, 5H), 2.21-2.26 (m, 1H), 2.28 (s, 3H), 2.49 (s, 3H),2.51-2.81 (m, 4H), 3.22-3.26 (m, 1H), 3.48-3.52 (m, 1H), 3.66 (s, 2H),3.87-3.93 (m, 1H), 4.15 (d, 1H, J=6 Hz), 4.19-4.24 (m, 1H), 6.93 (s,1H), 7.02 (d, 1H, J=3 Hz), 7.13 (s, 1H), 7.33-7.38 (m, 1H), 8.98 (br s,1H); ES-MS m/z 560 (M+H).

Example 161

Compound 1616-Chloro-N-(3-{4-[3-(3,5-dimethyl-isoxazol-4-yl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.87-0.91 (m, 1H), 0.99 (d, 3H, J=6 Hz), 1.01-1.09 (m,1H), 1.49-1.61 (m, 1H), 1.72-1.81 (m, 3H), 1.97 (s, 3H), 2.13 (s, 3H),2.19 (m, 1H), 2.29 (s, 3H), 2.51 (s, 3H), 2.61-2.66 (m, 1H), 2.72-2.80(m, 3H), 3.21-3.28 (m, 1H), 3.85 (s, 2H), 3.86-3.89 (m, 1H), 4.25-4.34(m, 1H), 5.37 (s, 1H), 6.93 (s, 1H), 7.11 (d, 1H, J=3 Hz), 7.25 (s, 1H),7.43-7.45 (m, 1H), 8.87 (br s, 1H); ES-MS m/z 573 (M+H).

Example 162

Compound 1626-Fluoro-2,4-dimethyl-N—{(R)-3-[4-(3-pyridin-3-yl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.92 (m, 1H), 0.94 (d, 3H, J=6 Hz),1.04-1.19 (m, 1H), 1.49-1.56 (m, 1H), 1.66 (s, 3H), 1.75-1.78 (m, 3H),2.21 (t, 1H, J=12 Hz), 2.33 (s, 3H), 2.47 (s, 3H), 2.62 (t, 1H, J=12Hz), 2.74-2.95 (m, 3H), 3.31 (t, 1H, J=12 Hz), 3.85-3.91 (m, 3H), 4.33(m, 1H), 6.32 (s, 1H), 6.44 (s, 1H), 7.05 (d, 1H, J=3 Hz), 7.19 (m, 1H),7.24 (d, 1H, J=3 Hz), 7.45 (m, 1H), 7.74 (m, 1H), 8.10 (d, 1H, J=3 Hz),8.20 (m, 1H), 8.81 (br s, 1H); ES-MS m/z 539 (M+H).

Example 163

Compound 1632,6-Dichloro-4-methyl-N—{(R)-3-[4-(1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 0.97 (m+d, 4H), 1.24 (m, 1H), 1.53 (m, 1H),1.67-1.76 (m, 4H), 2.15 (br t, 1H), 2.33 (s, 3H), 2.54 (br t, 1H), 2.75(m, 1H), 2.83-2.86 (m, 2H), 3.29 (m, 1H), 3.78 (m, 1H), 3.85 (s, 2H),4.19 (m, 1H), 4.43 (s, 2H), 7.00 (d, 1H, J=6.0 Hz), 7.05 (s, 1H), 7.12(d, 1H, J=3.0 Hz), 7.34 (m, 1H), 8.85 (br d, 1H); ES-MS m/z 498 (M+H).Anal. Calcd. for C₂₂H₂₉N₅O₂Cl₂S·0.25CH₄O: C, 52.77; H, 5.97; N, 13.83.Found: C, 53.12; H, 6.19; N, 13.45.

Example 164

Compound 1646-Cyano-2,4-dimethyl-N—{(R)-3-[4-(3-methyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

White foam. ¹H NMR (CDCl₃) δ 1.01 (br s, 3H), 1.44-1.74 (m, 5H),2.10-2.24 (m, 1H), 2.32 (s, 3H), 2.54 (s, 3H), 2.57-2.85 (m, 9H),3.26-3.31 (m, 1H), 3.67 (br s, 2H), 3.77-3.89 (m, 1H), 4.23 (br s, 2H),7.01 (d, 1H, J=5 Hz), 7.12 (br s, 1H), 7.25 (s, 1H), 7.38 (dd, 1H, J=5,3 Hz), 8.93 (br s, 1H); ES-MS m/z 483 (M+H).

Example 165

Compound 1652,4-Dichloro-6-methyl-N—{(R)-3-[4-(3-methyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-benzamide

¹H NMR (CDCl₃) δ 0.90-1.13 (m, 5H), 1.48 (m, 1H), 1.65-1.78 (m, 3H),2.12-2.20 (t, 1H, J=11.7 Hz), 2.30 (s, 3H), 2.53-2.60 (m, 1H), 2.66-2.67(d, 3H, J=4.5 Hz), 2.72-2.75 (m, 1H), 2.81-2.88 (m, 2H), 3.27-3.30 (m,1H), 3.68 (s, 2H), 3.88-3.90 (m, 1H), 4.17-4.18 (m, 1H), 4.26-4.29 (m,1H), 6.94-6.95 (m, 1H), 7.04 (s, 1H), 7.07-7.08 (m, 1H), 7.15-7.15 (m,1H), 7.35-7.36 (m, 1H), 8.86 (br s, 1H); ES-MS m/z 533 (M+Na).

Example 166

Compound 166 4,6-Dimethyl-pyridine-2,5-dicarboxylic acid2-isopropylamide5-({(R)-3-[4-(3-methyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

Hydrolysis of COMPOUND 164 gave the acid and subsequent EDCI couplingwith isopropylamine (similar procedure as used in EXAMPLE 210) affordedCOMPOUND 166. ¹H NMR (CDCl₃) δ 0.74 (m, 1H), 0.97 (d+m, 4H), 1.28 (d,6H, J=6.0 Hz), 1.53 (m, 1H), 1.72 (m, 3H), 2.15 (br t, 1H), 2.33 (s,3H), 2.55 (s+br t, 4H), 2.65 (s+m, 4H), 2.83 (m, 2H), 3.28 (m, 1H),3.48-3.52 (m, 2H), 3.91 (m, 1H), 4.13 (m, 1H), 4.28 (m, 1H), 6.98 (d,1H, J=6.0 Hz), 7.07 (s, 1H), 7.34 (m, 1H), 7.88 (s+m, 2H), 8.81 (br s,1H); ES-MS m/z 543 (M+H).

Examples 167 to 171 were prepared following the scheme below whereinR¹NH₂ is defined in the table and R² is as shown in the individualexamples.

TABLE 12

Example R¹NH₂  167* aminopyrazine 168 2-aminopyridine 1692-methoxyethylamine 170 3-aminoisoxazole 171 O-ethylhydroxylaminehydrochloride *= racemic

Example 167

Compound 1676-Chloro-2,4-dimethyl-N-{3-[4-(3-pyrazin-2-yl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

¹H NMR (CDCl₃) δ 0.92-0.96 (m, 1H), 0.99 (d, 3H, J=9 Hz), 1.12-1.19 (m,1H), 1.51-1.56 (m, 1H), 1.69-1.81 (m, 3H), 2.19-2.24 (m, 1H), 2.30 (s,3H), 2.51 (s, 3H), 2.56-2.63 (m, 1H), 2.69-2.79 (m, 3H), 3.23-3.29 (m,1H), 3.78-3.84 (m, 1H), 3.94 (d, 2H, J=6 Hz), 4.22-4.31 (m, 1H), 6.97(s, 1H), 7.02 (s, 1H), 7.09-7.15 (m, 1H), 7.24 (s, 1H), 7.38-7.45 (m,1H), 8.05-8.08 (m, 1H), 8.19 (s, 1H), 8.69 (br s, 1H), 9.31 (s, 1H);ES-MS m/z 556 (M+H).

Example 168

Compound 1686-Chloro-2,4-dimethyl-N—{(R)-3-[4-(3-pyridin-2-yl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

¹H NMR (CDCl₃) δ 0.87-0.96 (m, 1H), 0.99 (d, 3H, J=6-Hz), 1.04-1.15 (m,1H), 1.47-1.51 (m, 1H), 1.72-1.82 (m, 3H), 2.19-2.26 (m, 1H), 2.29 (s,3H), 2.50 (s, 3H), 2.52-2.59 (m, 1H), 2.72-2.81 (m, 3H), 3.22-3.31 (m,1H), 3.83-3.90 (m, 1H), 3.91 (d, 2H, J=12 Hz), 4.22-4.28 (m, 1H),6.84-6.89 (m, 1H), 6.98 (s, 1H), 7.02-7.07 (m, 2H), 7.22 (s, 1H),7.36-7.39 (m, 1H), 7.56-7.61 (m, 1H), 7.98 (d, 1H, J=6 Hz), 8.11-8.14(m, 1H), 8.72 (br s, 1H); ES-MS m/z 577 (M+Na).

Example 169

Compound 1696-Chloro-N—((R)-3-{4-[3-(2-methoxy-ethyl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.91-0.95 (m, 1H), 0.98 (d, 3H, J=6 Hz), 0.98-1.06 (m,1H), 1.47-1.51 (m, 1H), 1.55-1.73 (m, 3H), 2.07-2.17 (m, 1H), 2.28 (s,3H), 2.49 (s, 3H), 2.50-2.55 (m, 1H), 2.69-2.79 (m, 3H), 3.20 (s, 3H),3.33 (s, 4H), 3.33-3.39 (m, 1H), 3.70-3.74 (m, 2H), 3.87-3.96 (m, 1H),4.19-4.27 (m, 1H), 4.68 (br s, 1H), 6.93 (s, 1H), 7.01-7.04 (m, 1H),7.12 (br s, 1H), 7.32-7.36 (m, 1H), 8.84 (br s, 1H); ES-MS m/z 536(M+H).

Example 170

Compound 1706-Cyano-N—{(R)-3-[4-(3-isoxazol-3-yl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-2,4-dimethyl-1-oxy-nicotinamide

White solid. ¹H NMR (CDCl₃) δ 1.00-1.02 (d, 3H, J=6 Hz), 1.28-1.70 (m,4H), 1.74-1.91 (m, 3H), 2.17-2.32 (m, 1H), 2.34 (s, 3H), 2.41 (s, 3H),2.50-2.63 (m, 1H), 2.71-2.92 (m, 3H), 3.60-3.75 (m, 1H), 4.12-4.25 (m,1H), 4.29 (s, 2H), 6.91-6.92 (d, 1H, J=3 Hz), 6.99-7.01 (d, 1H, J=6 Hz),7.18 (s, 1H), 7.23 (s, 1H), 7.37-7.38 (d, 1H, J=3 Hz), 7.39 (s, 1H),8.14 (br s, 1H), 8.19-8.20 (d, 1H, J=3 Hz); ¹³C NMR (CDCl₃) δ 13.42,15.05, 18.39, 30.21, 30.67, 32.05, 35.21, 38.53, 42.45, 44.12, 44.79,50.92, 53.35, 53.66, 57.79, 76.53, 99.23, 111.51, 121.49, 123.95,125.87, 127.49, 129.60, 133.83, 138.44, 139.53, 147.02, 153.91, 157.26,158.72, 163.80; ES-MS m/z 574 (M+Na).

Example 171

Compound 1716-Chloro-2,4-dimethyl-N—{(R)-3-[4-(3-ethoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

¹H NMR (CDCl₃) δ 0.78-0.91 (m, 1H), 1.00 (d, 3H, J=6 Hz), 1.00-1.07 (m,1H), 1.17 (t, 3H, J=3 Hz), 1.46-1.51 (m, 1H), 1.61-1.75 (m, 3H),2.12-2.22 (m, 1H), 2.27 (s, 3H), 2.49 (s, 3H), 2.53-2.63 (m, 1H),2.65-2.74 (m, 1H), 2.79-2.87 (m, 2H), 3.23-3.31 (m, 1H), 3.68-3.72 (m,2H), 3.80 (q, 2H, J=6 Hz), 3.87-3.94 (m, 1H), 4.18-4.27 (m, 1H), 6.94(d, 2H, J=6 Hz), 7.04 (d, 1H, J=3 Hz), 7.12 (br s, 1H), 7.35-7.41 (m,1H), 8.78 (br s, 1H); ES-MS m/z 544 (M+Na).

Example 172

Compound 1726-Chloro-N—{(R)-3-[4-(3,3-dimethyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

To a solution of6-chloro-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(49 mg, 0.11 mmol) in 1,2-dichloroethane (5 ml) was added DIPEA (0.2 ml,1.15 mmol) followed by dimethyl carbamylchloride (60 μL, 0.34 mmol) andthe reaction stirred at 60° C. overnight. The solution was cooled,treated with saturated aqueous NaHCO₃ (25 ml) and extracted with CH₂Cl₂(3×15 ml). The combined organic extracts were dried (Na₂SO₄), filtered,and concentrated. Purification of the crude material by columnchromatography on silica gel (CH₂Cl₂/MeOH, 96:4 then 9:1) providedCOMPOUND 172 (18 mg, 32%) as a pale yellow foam. ¹H NMR (CDCl₃) δ1.01-1.07 (m, 3H), 1.53-1.79 (m, 5H), 2.15-2.25 (m, 1H), 2.30 (s, 3H),2.51 (s, 3H), 2.52-2.61 (m, 1H), 2.76 (s, 6H), 2.77-2.91 (m, 4H),3.35-3.46 (m, 2H), 3.70-3.98 (m, 3H), 6.92 (dd, 1H, J=4.8, 0.9 Hz), 6.96(s, 1H), 7.01-7.04 (m, 1H), 7.23 (dd, 1H, J=4.8, 3 Hz), 8.32 (br s, 1H);¹³C NMR (CDCl₃) δ 13.60, 19.26, 22.54, 29.76, 30.54, 31.52, 38.73,39.55, 43.50, 44.35, 52.28, 56.19, 60.34, 122.01, 122.86, 126.22,128.02, 133.32, 137.56, 148.09, 150.38, 155.79, 167.34, 182.46; ES-MSm/z 506 (M+H). Anal. Calcd. for C₂₅H₃₆N₅O₂SCl·0.9CH₃OH·0.1CH₂Cl₂: C,57.47; H, 7.38; N, 12.89. Found: C, 57.69; H, 7.02; N, 12.53.

Examples 173 to 175 were prepared following the scheme below whereinR¹NCO is defined in the table and R² is as shown in the individualexamples.

TABLE 13

Example R¹NCO 173 N-(trifluoroacetyl)piperidine-4-isocyanate 174 ethyl4-isocyanatobenzoate 175 methyl 3-isocyanatobenzoate

Example 173

Compound 1732,6-Dichloro-4-methyl-N—[(R)-3-(4-{1-thiophen-3-ylmethyl-3-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-yl]-ureido}-piperidin-1-yl)-butyl]-nicotinamide

¹H NMR (CDCl₃) δ 0.94-1.05 (m, 4H), 1.07-1.22 (m, 4H), 1.69-1.77 (m,3H), 1.86-1.99 (m, 2H), 2.11-2.24 (m, 1H), 2.34 (s, 3H), 2.58-2.69 (m,1H), 2.78-3.01 (m, 4H), 3.19-3.41 (m, 2H), 3.74-3.92 (m, 5H), 4.12-4.39(m, 3H), 6.98 (d, 1H, J=3 Hz), 7.04 (s, 1H), 7.12 (s, 1H), 7.36-7.41 (m,1H), 8.91 (br s, 1H); ES-MS m/z 677 (M+H).

Example 174

Compound 1744-[3-(1-{(R)-3-[(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-3-thiophen-3-ylmethyl-ureido]-benzoicacid ethyl ester

¹H NMR (CDCl₃) δ 0.83-1.17 (m, 5H), 1.36 (t, 3H, J=7.1 Hz), 1.48-1.85(m, 4H), 2.15-2.28 (m, 1H), 2.30 (s, 3H), 2.50 (s, 3H), 2.56-2.67 (m,1H), 2.71-2.93 (m, 3H), 3.23-3.36 (m, 1H), 3.79-3.96 (m, 3H), 4.26-4.39(m, 1H), 4.32 (q, 2H, J=7.1 Hz), 6.51 (br s, 1H), 6.95 (s, 1H), 7.12 (d,1H, J=3.9 Hz), 7.19 (d, 2H, J=8.8 Hz), 7.28 (dd, 1H, J=1.8, 0.9 Hz),7.46 (dd, 1H, J=5.1, 2.8 Hz), 7.89 (d, 2H, J=8.8 Hz), 8.83 (br s, 1H);ES-MS m/z 626 (M+H), 628 (M+H+2).

Example 175

Compound 1753-[3-(1-{(R)-3-[(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-3-thiophen-3-ylmethyl-ureido]-benzoicacid methyl ester

To a 0° C. solution of methyl 3-aminobenzoate (188 mg, 1.24 mmol) andNEt₃ (0.26 ml, 1.9 mmol) in CH₂Cl₂ (4 ml) was added triphosgene (375 mg,1.26 mmol). The resulting mixture was stirred at 0° C. for 15 minutesand at room temperature for an additional 2 hours. The solution wasdiluted with CH₂Cl₂ (30 ml) and was washed with H₂O (25 ml). The organicsolution was dried (Na₂SO₄), filtered and concentrated under reducedpressure, giving the crude isocyanate as a light yellow solid (222 mg,quantitative). ¹H NMR (CDCl₃) δ 3.90 (s, 3H), 7.24 (d, 1H, J=7.9 Hz),7.37 (t, 1H, J=7.9 Hz), 7.72 (s, 1H), 7.83 (d, 1H, J=7.9 Hz).

¹H NMR (CDCl₃) δ 0.84-1.15 (m, 2H), 0.98 (d, 3H, J=7.0 Hz), 1.47-1.57(m, 1H), 1.68-1.83 (m, 3H), 2.14-2.23 (m, 1H), 2.28 (s, 3H), 2.49 (s,3H), 2.55-2.63 (m, 1H), 2.69-2.89 (m, 3H), 3.21-3.32 (m, 1H), 3.80-3.95(m, 3H), 3.86 (s, 3H), 4.30 (tt, 1H, J=11.9, 3.5 Hz), 6.41 (s, 1H), 6.95(s, 1H), 7.12 (d, 1H, J=4.7 Hz), 7.24-7.30 (m, 2H), 7.41-7.46 (m, 2H),7.65 (d, 1H, J=7.7 Hz), 7.71 (s, 1H), 8.83 (br d, 1H, J=5.3 Hz); ES-MSm/z 612 (M+H), 614 (M+H+2).

Example 176

Compound 1764-[3-(1-{(R)-3-[(6-chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-3-thiophen-3-ylmethyl-ureido]-benzoicacid

A solution of4-[3-(1-{(R)-3-[(6-chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-3-thiophen-3-ylmethyl-ureido]-benzoicacid ethyl ester (COMPOUND 174) (32 mg, 0.051 mmol) and 3.8M NaOH (0.07ml, 0.27 mmol) in MeOH (0.45 ml) was stirred at 55° C. for 70 minutes.Once cooled, the reaction was diluted with H₂O (10 ml), the pH wasadjusted to 5 and the mixture was extracted with CHCl₃ (20 ml×4). Theorganic solution was dried (Na₂SO₄), filtered and concentrated underreduced pressure, giving COMPOUND 176 as a white solid (27.0 mg, 88%).¹H NMR (MeOH-d₄) δ 1.26 (d, 3H, J=6.6 Hz), 1.69-1.81 (m, 1H), 1.85-2.10(m, 4H), 2.35 (s, 3H), 2.49 (s, 3H), 2.68-2.78 (m, 1H), 2.82-2.93 (m,1H), 3.05-3.22 (m, 3H), 3.36-3.61 (m, 3H), 4.25-4.36 (m, 1H), 4.62 (s,2H), 7.10 (dd, 1H, J=5.0, 1.0 Hz), 7.26 (s, 1H), 7.28 (d, 1H, J=1.8 Hz),7.42 (d, 2H, J=8.8 Hz), 7.44 (dd, 1H, J=5.0, 3.2 Hz), 7.92 (d, 2H, J=8.8Hz); ES-MS m/z 598 (M+H), 600 (M+H+2).

Example 177

Compound 1773-[3-(1-{(R)-3-[(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-3-thiophen-3-ylmethyl-ureido]-benzoicacid

A solution of3-[3-(1-{(R)-3-[(6-chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-3-thiophen-3-ylmethyl-ureido]-benzoicacid methyl ester (COMPOUND 175) (47 mg, 0.077 mmol) and 3.8M NaOH (0.12ml, 0.46 mmol) in MeOH (0.65 ml) was stirred at 55° C. for 80 minutes.Once cooled, the reaction was diluted with H₂O (10 ml), the pH wasadjusted to 5 and the mixture was extracted with CHCl₃ (20 ml×4). Theorganic solution was dried (Na₂SO₄), filtered and concentrated underreduced pressure, giving COMPOUND 177 as a white solid (27.3 mg, 59%).¹H NMR (MeOH-d₄) δ 1.33 (d, 3H, J=6.0 Hz), 1.75-2.18 (m, 6H), 2.33 (s,3H), 2.48 (s, 3H), 2.86-3.08 (m, 2H), 3.20-3.38 (m, 3H), 3.41-3.60 (m,2H), 4.30-4.41 (m, 1H), 4.61 (s, 2H), 7.08 (d, 1H, J=4.7 Hz), 7.25 (s,1H), 7.26 (br s, 1H), 7.32-7.43 (m, 4H), 7.54 (d, 1H, J=8.0 Hz), 7.68(d, 1H, J=8.0 Hz), 7.92 (br s, 1H); ES-MS m/z 598 (M+H), 600 (M+H+2).

Example 178

Compound 1782,6-Dichloro-4-methyl-N—{(R)-3-[4-(3-(cyanomethoxy)-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

To a solution of N-hydroxyphthalimide (5.20 g, 31.88 mmol) in DMF (20ml) was added bromoacetonitrile (3.0 ml, 45.02 mmol) and Et₃N (10.0 ml,71.8 mmol) and the reaction stirred at room temperature for 2 d. Themixture was diluted with EtOAc (50 ml) and brine (40 ml) and the organiclayer was washed with brine (4×20 ml) and 1 N NaOH (30 ml), dried(Na₂SO₄) and concentrated to afford(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-acetonitrile (2.3 g, 36%) as abeige solid. ¹H NMR (CDCl₃) δ 4.96 (s, 2H), 7.80-7.84 (m, 2H), 7.89-7.92(m, 2H).

To a suspension of the phthalimide from above (1.15 g, 5.69 mmol) in1,2-dichloroethane (15 ml) was added hydrazine (0.20 ml, 6.43 mmol) andthe reaction stirred at 50° C. for 1 h then room temperature overnight.Another portion of hydrazine was added (0.20 ml, 6.43 mmol) and themixture heated to 60° C. for 3 additional h. The reaction was thencooled to 0° C. and filtered, washing with CH₂Cl₂. To the resultantfiltrate was added 1,1′-carbonyldiimidazole (0.82 g, 5.06 mmol) and thesolution heated to 60° C. for 2 h before adding2,6-dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(105 mg, 0.23 mmol) as a solid in one portion. The mixture was thenstirred at 60° C. overnight, cooled and diluted with 1 N NaOH (25 ml).The layers were separated and the aqueous layer was extracted withCH₂Cl₂ (2×10 ml). The combined organic extracts were dried (Na₂SO₄),concentrated and purified by column chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH, 96:4:0 then 9:1:0 then 88:10:2) followed by radialchromatography on silica gel (1 mm plate, CH₂Cl₂/MeOH/NH₄OH, 100:1:1then 50:1:1) to give COMPOUND 178 (45 mg, 35%) as a white foam. ¹H NMR(CDCl₃) δ 0.98-1.11 (m, 1H), 0.99 (d, 3H, J=6.6 Hz), 1.25-1.30 (m, 1H),1.51-1.58 (m, 1H), 1.70-1.79 (m, 3H), 2.18 (dt, 1H, J=11.7, 1.8 Hz),2.34 (s, 3H), 2.57 (dt, 1H, J=11.7, 1.8 Hz), 2.75-2.89 (m, 3H),3.31-3.35 (m, 1H), 3.78-3.85 (m, 1H), 3.87 (s, 2H), 4.10-4.18 (m, 1H),4.54 (s, 2H), 7.00 (dd, 1H, J=5.1, 1.2 Hz), 7.06 (br s, 1H), 7.14-7.16(m, 1H), 7.35 (br s, 1H), 7.41 (dd, 1H, J=5.1, 3 Hz), 8.64 (br d, 1H);¹³C NMR (CDCl₃) δ 13.83, 19.54, 30.25, 30.95, 40.46, 41.49, 43.70,51.98, 53.53, 60.49, 61.47, 115.86, 122.15, 124.79, 126.40, 128.30,132.87, 138.41, 146.96, 150.33, 151.32, 158.66, 164.48; ES-MS m/z 553(M+H). Anal. Calcd. for C₂₄H₃₀N₆O₃SCl₂·0.7CH₂Cl₂: C, 48.40; H, 5.16; N,13.71. Found: C, 48.31; H, 5.18; N, 13.42.

Examples 179 to 187 were prepared following the scheme below whereinR¹NHCO₂Ph or R¹NHCO₂PhNO₂ is defined in the table and R² is as shown inthe individual examples.

TABLE 14

Example R¹NHCO₂Ph or R¹NHCO₂PhNO₂ 179N-(4-nitrophenoxycarbonyl)isopropoxylamine 1804-[(4-nitro-phenoxycarbonylamino)-methyl]-benzoic acid 1814-[{(phenoxycarbonyl)amino}methyl]pyridine 182(1-oxy-pyridin-4-ylmethyl)-carbamic acid phenyl ester 183pyridin-3-ylmethyl-carbamic acid phenyl ester 184(1-oxy-pyridin-3-ylmethyl)-carbamic acid phenyl ester 185(5-methyl-pyrazin-2-ylmethyl)-carbamic acid phenyl ester 186(4-nitro-benzyl)-carbamic acid phenyl ester 187(1-oxy-pyridin-4-yl)-carbamic acid phenyl ester

Example 179

Compound 1792,6-Dichloro-N—{(R)-3-[4-(3-isopropoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-4-methyl-nicotinamide

To a suspension of N-hydroxyphthalimide (2.52 g, 15.45 mmol) in THF (60ml) was added triphenylphosphine (4.10 g, 15.63 mmol), 2-propanol (1.2ml, 15.67 mmol) and diethyl azodicarboxylate (2.68 ml, 17.0 mmol) andthe reaction stirred overnight. The mixture was concentrated andpurified by column chromatography on silica gel (Hexanes/EtOAc, 4:1) toafford 2-isopropoxy-isoindole-1,3-dione (2.59 g, 82%) as a white solid.¹H NMR (CDCl₃) δ 1.38 (d, 6H, J=6 Hz), 4.52-4.58 (m, 1H), 7.73-7.76 (m,2H), 7.83-7.85 (m, 2H).

To a solution of the phthalimide from above (2.56 g, 12.5 mmol) inCH₂Cl₂ (12 ml) was added methylhydrazine (0.70 ml, 13.16 mmol) and thereaction stirred at room temperature overnight. The resultant suspensionwas then filtered, washing with Et₂O and the filtrate concentrated invacuo (careful product is volatile) to provide O-isopropyl-hydroxylamine(200 mg) as a yellow oil.

To as solution of the crude O-isopropyl-hydroxylamine (200 mg) fromabove in CH₂Cl₂ (5 ml) was added Et₃N (0.30 ml, 2.16 mmol) and4-nitrophenyl chloroformate (430 mg, 2.13 mmol) and the mixture stirredat room temperature for 30 min. before diluting with CH₂Cl₂ (20 ml) andbrine (15 ml). The aqueous layer was extracted with CH₂Cl₂ (1×15 ml) andthe combined organic extracts dried (Na₂SO₄), concentrated and purifiedby column chromatography on silica gel (Hexanes/EtOAc, 4:1) to affordN-(4-nitrophenoxycarbonyl)isopropoxylamine (290 mg) as a yellow oil.

COMPOUND 179 was isolated as a yellow foam. ¹H NMR (CDCl₃) δ 0.91-1.03(m, 1H), 0.98 (d, 3H, J=6.6 Hz), 1.12 (d, 6H, J=6 Hz), 1.15-1.25 (m,1H), 1.48-1.55 (m, 1H), 1.68-1.78 (m, 3H), 2.16 (br t, 1H, J=11.1 Hz),2.32 (s, 3H), 2.55 (br t, 1H, J=11.1 Hz), 2.72-2.86 (m, 3H), 3.26-3.31(m, 1H), 3.79-3.83 (m, 1H), 3.80 (s, 2H), 3.93-3.98 (m, 1H), 4.13-4.25(m, 1H), 6.86 (s, 1H), 6.99 (d, 1H, J=4.8 Hz), 7.03 (s, 1H), 7.11 (br s,1H), 7.37 (dd, 1H, J=4.8, 3 Hz), 8.83 (br d, 1H); ¹³C NMR (CDCl₃) δ13.82, 19.53, 20.84, 30.30, 30.75, 31.08, 40.62, 41.49, 43.67, 52.15,52.86, 60.74, 77.01, 121.74, 124.71, 126.38, 127.93, 132.99, 139.31,147.05, 150.22, 151.29, 159.59, 164.43; ES-MS m/z 556 (M+H). Anal.Calcd. for C₂₅H₃₅N₅O₃SCl₂·0.6CH₂Cl₂: C, 50.61; H, 6.01; N, 11.53. Found:C, 50.88; H, 5.99; N, 11.41.

Example 180

Compound 1804-[3-(1-{(R)-3-[(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-3-thiophen-3-ylmethyl-ureidomethyl]-benzoicacid

To a stirred slurry of 4-aminomethyl benzoic acid (1.51 g, 10 mmol) andNaHCO₃ (2.0 g, 24 mmol) in H₂O (30 ml) was added a solution of4-nitrophenyl chloroformate (2.02 g, 10 mmol) in CH₂Cl₂ (25 ml) at roomtemperature. The mixture was stirred for 3 hours and then concentratedunder reduced pressure. The mixture was diluted with H₂O (100 ml) andconc. HCl was added to pH˜1. The mixture was filtered and the solid wasdried in vacuo. Purification by column chromatography on silica gel(10:0 to 9:1, CH₂Cl₂/MeOH) afforded the desired nitrophenylcarbamate asa white solid (1.03 g, 29%).

¹H NMR (CD₃OD) δ 1.29 (d, 3H, J=6.6 Hz), 1.75-2.02 (m, 5H), 2.33 (s,3H), 2.47 (s, 3H), 2.82 (t, 1H, J=11.0 Hz), 2.95 (t, 1H, J=11.0 Hz),3.15-3.28 (m, 3H), 3.42-3.61 (m, 3H), 4.22-4.35 (m, 1H), 4.43 (s, 2H),4.48 (s, 2H), 6.83 (br s, 1H), 7.01 (d, 1H, J=5.1 Hz), 7.16 (d, 1H,J=3.0 Hz), 7.23 (d, 2H, J=8.1 Hz), 7.25 (s, 1H), 7.39 (dd, 1H, J=3.0,5.1 Hz), 7.89 (d, 2H, J=8.1 Hz); ¹³C NMR (CD₃OD) δ 12.81, 17.90, 20.91,28.64, 28.84, 31.59, 37.05, 42.02, 44.13, 46.57, 49.99, 52.26, 59.12,121.28, 122.98, 126.40, 126.72 (2C), 129.60 (2C), 144.15; ES-MS m/z 612(M+H). Anal Calcd. for C₃₁H₃₈N₅SO₄Cl·0.5H₂O: C, 59.94; H, 6.33; N,11.27. Found: C, 59.61; H, 6.38; N, 11.44.

Example 181

Compound 1816-Chloro-2,4-dimethyl-N—{(R)-3-[4-(3-pyridin-4-ylmethyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

To a 0° C. solution of 4-(aminomethyl)pyridine (0.50 ml, 5.0 mmol) andNEt₃ (1.0 ml, 7.2 mmol) in CH₂Cl₂ (25 ml) was added dropwise phenylchloroformate (0.60 ml, 4.8 mmol) (Yoakim, C.; Ogilvie, W. W.; Cameron,D. R.; Chabot, C.; Guse, I.; Haché, B.; Naud, J.; O'Meara, J. A.;Plante, R.; Déziel, R. J. Med. Chem., 1998, 41, 2882-2891). Theresulting yellow solution was stirred at 0° C. for 60 minutes and mostof the solvent was removed under reduced pressure. The residue was takenup into EtOAc (75 ml) and washed with H₂O (50 ml) and brine (50 ml). Theorganic solution was dried (Na₂SO₄), filtered and concentrated underreduced pressure. Purification by flash column chromatography on silica(CH₂Cl₂/MeOH, 19:1) gave the carbamate as a yellow solid (704 mg, 64%).¹H NMR (CDCl₃) δ 4.44 (d, 2H, J=6.2 Hz), 5.90 (br s, 1H), 7.13-7.26 (m,5H), 7.33-7.39 (m, 2H), 8.56 (d, 2H, J=5.6 Hz).

COMPOUND 181 was isolated as a white foam. ¹H NMR (CDCl₃) δ 0.78-0.92(m, 1H), 0.94-1.10 (m, 1H), 0.98 (d, 3H, J=6.6 Hz), 1.47-1.56 (m, 1H),1.65-1.80 (m, 3H), 2.11-2.21 (m, 1H), 2.28 (s, 3H), 2.49 (s, 3H),2.52-2.62 (m, 1H), 2.67-2.75 (m, 1H), 2.78-2.87 (m, 2H), 3.21-3.31 (m,1H), 3.73 (d, 1H, J=17.7 Hz), 3.80 (d, 1H, J=17.7 Hz), 3.83-3.93 (m,1H), 4.23-4.34 (m, 1H), 4.31 (d, 2H, J=5.6 Hz), 4.74 (br t, 1H, J=5.7Hz), 6.93-6.97 (m, 3H), 7.06 (dd, 1H, J=4.8, 0.9 Hz), 7.14 (d, 1H, J=1.2Hz), 7.39 (dd, 1H, J=4.8, 2.6 Hz), 8.46 (d, 2H, J=6.4 Hz), 8.91 (br d,1H, J=6.0 Hz); ¹³C NMR (CDCl₃) δ 13.34, 18.65, 21.94, 29.92, 30.35,30.91, 40.10, 41.30, 43.17, 43.42, 51.77, 51.97, 60.52, 121.22, 121.74,122.31, 125.98, 127.34, 132.85, 139.26, 147.49, 148.57, 149.67, 149.87,155.29, 157.68, 166.84; ES-MS m/z 569 (M+H), 571 (M+H+2).

Example 182

Compound 1826-Chloro-2,4-dimethyl-N—((R)-3-{4-[3-(1-oxy-pyridin-4-ylmethyl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-nicotinamide

A solution of 4-[{(phenoxycarbonyl)amino}methyl]pyridine (230 mg, 1.01mmol) and MMPP (80%, 623 mg, 1.01 mmol) in MeOH (3.5 ml) and CH₂Cl₂ (3.5ml) was stirred at room temperature for 4 hours. After the first 1.5hours, an additional portion (127 mg, 0.21 mmol) of MMPP was added. Thereaction was diluted with saturated aqueous NaHCO₃ (30 ml) and wasextracted with CH₂Cl₂ (25 ml×3). The combined organic solution was dried(Na₂SO₄), filtered and concentrated under reduced pressure, giving thecrude N-oxide as a white solid (206 mg, 0.84 mmol, 84%). ¹H NMR (CDCl₃)δ 4.43 (d, 2H, J=6.2 Hz), 5.84 (br s, 1H), 7.13 (d, 2H, J=7.9 Hz),7.19-7.29 (m, 3H), 7.34-7.40 (m, 2H), 8.17 (d, 2H, J=7.1 Hz).

COMPOUND 182 was isolated as a white foam. ¹H NMR (CDCl₃) δ 0.77-1.12(m, 2H), 0.98 (d, 3H, J=6.6 Hz), 1.47-1.82 (m, 4H), 2.11-2.22 (m, 1H),2.28 (s, 3H), 2.49 (s, 3H), 2.56-2.63 (m, 1H), 2.67-2.89 (m, 3H),3.21-3.33 (m, 1H), 3.71-3.92 (m, 3H), 4.20-4.33 (m, 1H), 4.25 (d, 2H,J=6.3 Hz), 4.80 (br s, 1H), 6.93 (s, 1H), 6.95 (d, 2H, J=6.6 Hz), 7.04(d, 1H, J=5.1 Hz), 7.13 (d, 1H, J=1.2 Hz), 7.39 (dd, 1H, J=5.0, 2.9 Hz),8.05 (d, 2H, J=6.6 Hz), 8.87 (br s, 1H); ¹³C NMR (CDCl₃) δ 13.36, 18.66,21.94, 29.88, 30.49, 30.81, 39.91, 41.32, 42.75, 43.30, 51.66, 52.10,60.33, 121.16, 122.31, 124.46, 126.04, 127.33, 132.85, 138.66, 139.32,139.45, 147.52, 149.82, 155.28, 157.57, 166.87; ES-MS m/z 585 (M+H), 587(M+H+2).

Example 183

Compound 1836-Chloro-2,4-dimethyl-N—{(R)-3-[4-(3-pyridin-3-ylmethyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

To a 0° C. solution of 3-(aminomethyl)pyridine (0.50 ml, 4.9 mmol) andNEt₃ (1.0 ml, 7.2 mmol) in CH₂Cl₂ (25 ml) was added dropwise phenylchloroformate (0.65 ml, 5.2 mmol). The resulting yellow solution wasstirred at 0° C. for 60 minutes and most of the solvent was then removedunder reduced pressure. The residue was taken up into EtOAc (75 ml) andwashed with H₂O (50 ml) and brine (50 ml). The organic solution wasdried (Na₂SO₄), filtered and concentrated under reduced pressure.Purification by flash column chromatography on silica (CH₂Cl₂/MeOH,19:1) gave the carbamate as a white solid (923 mg, 83%). ¹H NMR (CDCl₃)δ 4.43 (d, 2H, J=6.2 Hz), 5.84 (br s, 1H), 7.12 (d, 2H, J=7.9 Hz), 7.19(t, 1H, J=7.4 Hz), 7.27 (dd, 1H, J=8.1, 4.6 Hz), 7.35 (d, 2H, J=7.6 Hz),7.69 (d, 1H, J=8.0 Hz), 8.53 (d, 1H, J=4.9 Hz), 8.56 (s, 1H).

COMPOUND 183 was isolated as a white foam. ¹H NMR (CDCl₃) δ 0.76-1.09(m, 2H), 0.98 (d, 3H, J=6.6 Hz), 1.46-1.56 (m, 1H), 1.63-1.80 (m, 3H),2.11-2.21 (m, 1H), 2.28 (s, 3H), 2.49 (s, 3H), 2.53-2.62 (m, 1H),2.66-2.75 (m, 1H), 2.76-2.88 (m, 2H), 3.20-3.31 (m, 1H), 3.70 (d, 1H,J=18.0 Hz), 3.78 (d, 1H, J=18.0 Hz), 3.82-3.93 (m, 1H), 4.21-4.34 (m,1H), 4.31 (d, 2H, J=5.6 Hz), 4.69 (t, 1H, J=5.9 Hz), 6.94 (s, 1H), 7.03(d, 1H, J=4.8 Hz), 7.10 (d, 1H, J=0.9 Hz), 7.18 (dd, 1H, J=7.8, 5.1 Hz),7.35 (dd, 1H, J=4.8, 3.0 Hz), 7.40 (d, 1H, J=8.0 Hz), 8.35 (s, 1H), 8.46(d, 1H, J=4.5 Hz), 8.90 (br d, 1H, J=4.8 Hz); ¹³C NMR (CDCl₃) δ 13.38,18.68, 21.98, 29.92, 30.32, 30.94, 40.20, 41.30, 42.19, 43.15, 51.85,51.95, 60.66, 121.19, 122.36, 123.31, 125.98, 127.33, 132.87, 134.90,134.98, 139.26, 147.52, 148.44, 148.79, 149.94, 155.33, 157.76, 166.89;ES-MS m/z 569 (M+H), 571 (M+H+2).

Example 184

Compound 1846-Chloro-2,4-dimethyl-N—((R)-3-{4-[3-(1-oxy-pyridin-3-ylmethyl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-nicotinamide

A solution of pyridin-3-ylmethyl-carbamic acid phenyl ester (240 mg,1.05 mmol) and MMPP (80%, 782 mg, 1.26 mmol) in MeOH (3.5 ml) and CH₂Cl₂(3.5 ml) was stirred at room temperature for 4 hours. The reaction wasdiluted with saturated aqueous NaHCO₃ (25 ml) and was extracted withCH₂Cl₂ (25 ml×3). The combined organic solution was washed with brine(30 ml), was dried (Na₂SO₄), filtered and concentrated under reducedpressure. Purification by flash column chromatography on silica(CH₂Cl₂/MeOH, 14:1) gave the N-oxide as a white solid (213 mg, 83%). ¹HNMR (CDCl₃) δ 4.41 (d, 2H, J=6.2 Hz), 6.35 (br s, 1H), 7.11 (d, 2H,J=8.4 Hz), 7.18-7.39 (m, 5H), 8.14 (d, 1H, J=6.1 Hz), 8.23 (s, 1H).

COMPOUND 184 was isolated as a white foam. ¹H NMR (CDCl₃) δ 0.78-1.10(m, 2H), 0.97 (d, 3H, J=6.6 Hz), 1.46-1.56 (m, 1H), 1.62-1.84 (m, 3H),2.09-2.20 (m, 1H), 2.28 (s, 3H), 2.47 (s, 3H), 2.50-2.60 (m, 1H),2.66-2.75 (m, 1H), 2.76-2.87 (m, 2H), 3.20-3.32 (m, 1H), 3.74 (d, 1H,J=18.3 Hz), 3.78-3.90 (m, 1H), 3.81 (d, 1H, J=18.3 Hz), 4.17-4.29 (m,1H), 4.24 (d, 2H, J=5.6 Hz), 4.89 (t, 1H, J=5.5 Hz), 6.96 (s, 1H),6.99-7.06 (m, 2H), 7.10-7.16 (m, 2H), 7.37 (dd, 1H, J=4.9, 3.0 Hz), 7.95(s, 1H), 8.01 (d, 1H, J=6.2 Hz), 8.85 (br d, 1H, J=5.3 Hz); ES-MS m/z585 (M+H), 587 (M+H+2).

Example 185

Compound 1856-Chloro-2,4-dimethyl-N—((R)-3-{4-[3-(5-methyl-pyrazin-2-ylmethyl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-nicotinamide

To a 0° C. solution of 2-(aminomethyl)-5-methylpyrazine (137 mg, 1.11mmol) and NEt₃ (0.22 ml, 1.6 mmol) in CH₂Cl₂ (5 ml) was added dropwisephenyl chloroformate (0.15 ml, 1.2 mmol). The reaction was stirred at 0°C. for 70 minutes and then was diluted with CH₂Cl₂ (50 ml) and washedwith saturated aqueous NaHCO₃ (25 ml) and brine (25 ml). The organicsolution was dried (Na₂SO₄), filtered and concentrated under reducedpressure. Purification by flash column chromatography on silica(CH₂Cl₂/MeOH, 29:1) gave the carbamate as a yellow solid (162 mg, 60%).¹H NMR (CDCl₃) δ 2.58 (s, 3H), 4.58 (d, 2H, J=5.8 Hz), 6.02 (br s, 1H),7.13 (d, 2H, J=7.9 Hz), 7.20 (t, 1H, J=7.2 Hz), 7.36 (t, 2H, J=7.8 Hz),8.42 (s, 1H), 8.52 (s, 1H).

COMPOUND 185 was isolated as a white foam. ¹H NMR (CDCl₃) δ 0.77-1.09(m, 2H), 0.97 (d, 3H, J=6.6 Hz), 1.46-1.56 (m, 1H), 1.62-1.80 (m, 3H),2.10-2.20 (m, 1H), 2.28 (s, 3H), 2.49 (s, 3H), 2.50-2.61 (m, 1H), 2.52(s, 3H), 2.65-2.74 (m, 1H), 2.76-2.87 (m, 2H), 3.19-3.31 (m, 1H), 3.74(d, 1H, J=17.9 Hz), 3.81-3.92 (m, 1H), 3.82 (d, 1H, J=17.9 Hz), 4.24(tt, 1H, J=12.0, 3.9 Hz), 4.42 (d, 2H, J=5.3 Hz), 5.25 (t, 1H, J=5.1Hz), 6.94 (s, 1H), 7.06 (d, 1H, J=5.1 Hz), 7.15 (d, 1H, J=1.2 Hz), 7.34(dd, 1H, J=4.8, 3.1 Hz), 8.27 (s, 1H), 8.33 (s, 1H), 8.88 (br d, 1H,J=5.8 Hz); ¹³C NMR (CDCl₃) δ 13.38, 18.70, 21.12, 22.00, 29.94, 30.33,30.97, 40.24, 41.42, 43.18, 43.50, 51.92, 52.03, 60.70, 121.43, 122.40,126.12, 126.94, 132.86, 139.27, 142.35, 143.28, 147.49, 150.02, 150.35,151.98, 155.34, 157.96, 166.94; ES-MS m/z 584 (M+H), 586 (M+H+2).

Example 186

Compound 1866-Chloro-2,4-dimethyl-N—((R)-3-{4-[3-(4-nitro-benzyl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-nicotinamide

To a 0° C. solution of 4-nitrobenzylamine hydrochloride (382 mg, 2.03mmol) and NEt₃ (0.70 ml, 5.0 mmol) in CH₂Cl₂ (10 ml) was added dropwisephenyl chloroformate (0.27 ml, 2.2 mmol). The resulting suspension wasstirred at 0° C. for 35 minutes. Following dilution with saturatedaqueous NaHCO₃ (30 ml) the mixture was extracted with CH₂Cl₂ (25 ml×3).The combined organic solution was washed with brine (50 ml), was dried(Na₂SO₄), filtered and concentrated under reduced pressure. Purificationby flash column chromatography on silica (CH₂Cl₂/Et₂O, 19:1) gave thecarbamate as a white solid (370 mg, 67%). ¹H NMR (CDCl₃) δ 4.56 (d, 2H,J=6.1 Hz), 5.50 (br s, 1H), 7.15 (d, 2H, J=7.9 Hz), 7.22 (t, 1H, J=7.4Hz), 7.37 (t, 2H, J=7.9 Hz), 7.52 (d, 2H, J=8.6 Hz), 8.23 (d, 2H, J=8.6Hz).

COMPOUND 186 was isolated as a white solid. ¹H NMR (CDCl₃) δ 0.78-1.10(m, 2H), 0.98 (d, 3H, J=7.0 Hz), 1.47-1.57 (m, 1H), 1.65-1.80 (m, 3H),2.11-2.20 (m, 1H), 2.28 (s, 3H), 2.50 (s, 3H), 2.52-2.62 (m, 1H),2.67-2.75 (m, 1H), 2.78-2.88 (m, 2H), 3.21-3.31 (m, 1H), 3.73 (d, 1H,J=18.6 Hz), 3.80 (d, 1H, J=18.6 Hz), 3.83-3.93 (m, 1H), 4.28 (tt, 1H,J=12.3, 4.0 Hz), 4.39 (d, 2H, J=5.7 Hz), 4.79 (t, 1H, J=5.9 Hz), 6.94(s, 1H), 7.06 (dd, 1H, J=5.0, 0.8 Hz), 7.13 (dd, 1H, J=2.6, 1.1 Hz),7.20 (d, 2H, J=8.7 Hz), 7.39 (dd, 1H, J=5.1, 2.9 Hz), 8.11 (d, 2H, J=8.7Hz), 8.90 (br d, 1H, J=5.4 Hz); ¹³C NMR (CDCl₃) δ 13.38, 18.70, 22.00,29.95, 30.34, 30.97, 40.23, 41.32, 43.14, 43.99, 51.85, 51.99, 60.69,121.31, 122.35, 123.64, 126.02, 127.46, 127.62, 132.92, 139.24, 146.90,147.23, 147.57, 149.92, 155.37, 157.67, 166.86; ESI-MS m/z 613 (M+H),615 (M+H+2).

Example 187

Compound 1876-Chloro-2,4-dimethyl-N—((R)-3-{4-[3-(1-oxy-pyridin-4-yl)-1-thiophen-3-ylmethyl-ureido]-piperidin-1-yl}-butyl)-nicotinamide

A solution of 4-aminopyridine (482 mg, 5.12 mmol), phenyl chloroformate(0.70 ml, 5.6 mmol) and NEt₃ (1.0 ml, 7.2 mmol) in CH₂Cl₂ (25 ml) wasstirred at room temperature for 2.5 hours. The reaction was diluted withsaturated aqueous NaHCO₃ (50 ml) and extracted with CH₂Cl₂ (30 ml×3).The combined organic solution was washed with brine (50 ml), was dried(Na₂SO₄), filtered and concentrated under reduced pressure, giving thecrude carbamate as an off-white powder (994 mg, 91%). ¹H NMR (CDCl₃) δ7.19 (d, 2H, J=8.2 Hz), 7.25-7.30 (m, 1H), 7.33 (br s, 1H), 7.39-7.45(m, 4H), 8.52 (d, 2H, J=6.4 Hz).

A solution of pyridin-4-yl-carbamic acid phenyl ester (262 mg, 1.22mmol) and MMPP (80%, 895 mg, 1.45 mmol) in MeOH (4.0 ml) and CH₂Cl₂ (4.0ml) was stirred at room temperature for 6 hours. The reaction wasdiluted with saturated aqueous NaHCO₃ (30 ml) and was extracted withCH₂Cl₂ (25 ml×3). The combined organic solution was washed with brine(50 ml), was dried (Na₂SO₄), filtered and concentrated under reducedpressure. Purification by flash column chromatography on silica(CH₂Cl₂/MeOH, 14:1, increased to 9:1) gave the N-oxide as a white solid(94.1 mg, 0.41 mmol, 34%). ¹H NMR (MeOH-d₄) δ 7.24 (d, 2H, J=8.3 Hz),7.31 (t, 1H, J=7.4 Hz), 7.46 (t, 2H, J=7.9 Hz), 7.75 (d, 2H, J=7.0 Hz),8.29 (d, 2H, J=7.0 Hz).

COMPOUND 187 was isolated as a white solid. ¹H NMR (CDCl₃) δ 0.87-1.19(m, 2H), 1.00 (d, 3H, J=6.6 Hz), 1.49-1.58 (m, 1H), 1.67-1.83 (m, 3H),2.15-2.25 (m, 1H), 2.29 (s, 3H), 2.49 (s, 3H), 2.55-2.65 (m, 1H),2.71-2.91 (m, 3H), 3.23-3.34 (m, 1H), 3.81-3.93 (m, 1H), 3.89 (s, 2H),4.27 (tt, 1H, J=12.1, 4.0 Hz), 6.79 (s, 1H), 6.94 (s, 1H), 7.09 (dd, 1H,J=5.0, 1.1 Hz), 7.15 (d, 2H, J=7.4 Hz), 7.24-7.28 (m, 1H), 7.45 (dd, 1H,J=4.7, 3.2 Hz), 7.95 (d, 2H, J=7.4 Hz), 8.76 (br d, 1H, J=4.8 Hz); ¹³CNMR (CDCl₃) δ 13.44, 18.68, 21.97, 29.92, 30.68, 30.81, 39.80, 41.52,43.41, 51.51, 52.77, 60.07, 115.59, 121.49, 122.37, 126.09, 127.61,132.81, 138.59, 138.92, 139.49, 147.53, 149.90, 154.43, 155.24, 166.94;ES-MS m/z 571 (M+H), 573 (M+H+2).

Example 188

Compound 1886-Chloro-N—{(R)-3-[4-(3-hydroxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

To a solution of6-chloro-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(62 mg, 0.14 mmol) in THF (5 ml) was addedN-(4-nitrophenoxycarbonyl)hydroxylamine (42 mg, 0.21 mmol) and theresultant mixture stirred at 70° C. for 5.5 h. The mixture wasconcentrated and purified by column chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH, 96:4:0 then 9:1:0 then 88:10:2) followed by radialchromatography on silica gel (1 mm plate, CH₂Cl₂/CH₃OH/NH₄OH, 100:1:1)to give COMPOUND 188 (63 mg, 91%) as a yellow foam. ¹H NMR (CDCl₃) δ0.99-1.01 (m, 1H), 0.99 (d, 3H, J=6.6 Hz), 1.13-1.17 (m, 1H), 1.50-1.76(m, 5H), 2.13-2.21 (m, 1H), 2.28 (s, 3H), 2.48 (s, 3H), 2.52-2.61 (m,1H), 2.71-2.86 (m, 3H), 3.25-3.34 (m, 1H), 3.78-3.85 (m, 3H), 4.09-4.17(m, 1H), 6.60 (s, 1H), 6.92 (s, 1H), 7.01 (d, 1H, J=4.8 Hz), 7.12 (s,1H), 7.37-7.39 (m, 1H), 8.58 (br d, 1H); ¹³C NMR (CDCl₃) δ 13.32, 18.76,22.05, 29.65, 30.49, 30.90, 39.80, 41.00, 43.25, 51.60, 53.04, 60.04,121.45, 122.43, 126.04, 127.60, 132.76, 138.36, 147.54, 150.07, 155.34,161.29, 167.15; ES-MS m/z 494 (M+H). Anal. Calcd. forC₂₃H₃₂N₅O₃SCl·0.3CH₂Cl₂: C, 53.87; H, 6.32; N, 13.48. Found: C, 54.25;H, 6.42; N, 13.12.

Example 189

Compound 1894-[3-(1-{3-[(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-3-thiophen-3-ylmethyl-ureidomethyl]-benzoicacid methyl ester

A solution of methyl 4-(bromomethyl)benzoate (1.04 g, 4.54 mmol) andNaN₃ (349 mg, 5.37 mmol) in DMF (12 ml) was stirred at 80° C. for 80minutes. Once cooled, the reaction was diluted with brine (30 ml) andwas extracted with 1:1 Et₂O/hexane (25 ml×3). The combined organicsolution was washed with H₂O (50 ml), was dried (Na₂SO₄), filtered andconcentrated under reduced pressure, giving the crude azide as acolorless liquid (854 mg, 98%). ¹H NMR (CDCl₃) δ 3.93 (s, 3H), 4.42 (s,2H), 7.39 (d, 2H, J=8.2 Hz), 8.06 (d, 2H, J=8.2 Hz).

A solution of the crude azide (854 mg, 4.47 mmol), PPh₃ (1.26 g, 4.80mmol) and H₂O (3 ml) in THF (19 ml) was stirred at room temperature for17 hours. The reaction was taken up in 1M HCl (30 ml) and this mixturewas washed with Et₂O (25 ml×3). The aqueous solution was made basic with1.5M NaOH (30 ml) and was extracted with CH₂Cl₂ (25 ml×3). This organicsolution was dried (Na₂SO₄), filtered and concentrated under reducedpressure. Purification by flash column chromatography on silica(CH₂Cl₂/MeOH, 19:1, increased to CH₂Cl₂/MeOH/NH₄OH, 19:1:0.2) gave thebenzyl amine as a light yellow liquid (352 mg, 48%). ¹H NMR (CDCl₃) δ1.47 (s, 2H), 3.91 (s, 3H), 3.94 (s, 2H), 7.39 (d, 2H, J=8.1 Hz), 8.01(d, 2H, J=8.1 Hz).

To a solution of the benzyl amine (179 mg, 1.08 mmol) and DIPEA (0.45ml, 2.6 mmol) in CH₂Cl₂ (5 ml) was carefully added triphosgene (150 mg,0.51 mmol) and the resulting solution was stirred at room temperaturefor 20 minutes (Majer, P.; Randad, R. S. J. Org. Chem., 1994, 59,1937-1938). A solution of4-[(thiophen-3-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butylester (455 mg, 1.53 mmol) in CH₂Cl₂ (2 ml) was then added and thereaction was stirred at room temperature for an additional 18 hours. Themixture was diluted with saturated aqueous NaHCO₃ (25 ml) and wasextracted with CH₂Cl₂ (20 ml×3). The combined organic solution waswashed with brine (50 ml), was dried (Na₂SO₄), filtered and concentratedunder reduced pressure. Purification by flash column chromatography onsilica (CH₂Cl₂/Et₂O, 9:1, increased to 3:1) gave the urea as a lightyellow foam (236 mg, 45%). ¹H NMR (CDCl₃) δ 1.43 (s, 9H), 1.44-1.58 (m,2H), 1.69-1.79 (m, 2H), 2.71-2.85 (m, 2H), 3.89 (s, 3H), 4.09-4.24 (m,2H), 4.33 (s, 2H), 4.39 (d, 2H, J=5.8 Hz), 4.54 (tt, 1H, J=12.0, 3.7Hz), 4.80 (t, 1H, J=5.7 Hz), 6.95 (d, 1H, J=4.8 Hz), 7.07 (d, 1H, J=1.5Hz), 7.13 (d, 2H, J=8.5 Hz), 7.34 (dd, 1H, J=5.0, 2.9 Hz), 7.91 (d, 2H,J=8.5 Hz).

A solution of the tert-butyl carbamate (236 mg, 0.48 mmol) and TFA (0.50ml) in CH₂Cl₂ (2.5 ml) was stirred at room temperature for 60 minutes.The reaction was made basic with 0.5M NaOH (25 ml) and was extractedwith CH₂Cl₂ (20 ml×3). The organic solution was dried (Na₂SO₄), filteredand concentrated under reduced pressure. Purification by flash columnchromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 14:1:0.15) gave thepiperidine as a white foam (146 mg, 78%). ¹H NMR (CDCl₃) δ 1.55 (qd, 2H,J=12.2, 4.1 Hz), 1.64 (s, 1H), 1.72-1.81 (m, 2H), 2.71 (td, 2H, J=12.1,2.2 Hz), 3.07-3.16 (m, 2H), 3.90 (s, 3H), 4.39 (s, 2H), 4.40 (d, 2H,J=5.7 Hz), 4.45 (tt, 1H, J=12.2, 4.0 Hz), 4.76 (t, 1H, J=5.7 Hz), 6.97(dd, 1H, J=5.0, 1.1 Hz), 7.07-7.10 (m, 1H), 7.15 (d, 2H, J=8.2 Hz), 7.33(dd, 1H, J=5.0, 2.9 Hz), 7.92 (d, 2H, J=8.2 Hz).

A solution of4-(3-piperidin-4-yl-3-thiophen-3-ylmethyl-ureidomethyl)-benzoic acidmethyl ester (97 mg, 0.25 mmol), 2-(3-oxo-butyl)-isoindole-1,3-dione(109 mg, 0.50 mmol) and glacial AcOH (5 drops) in MeOH (1.2 ml) at 60°C. was added NaBH₃CN (50 mg, 0.80 mmol) and the reaction was stirred for20.5 hours. The reaction was cooled, diluted with saturated aqueousNaHCO₃ (25 ml) and was extracted with CH₂Cl₂ (20 ml×3). The combinedorganic solution was dried (Na₂SO₄), filtered and concentrated underreduced pressure. Purification by flash column chromatography on silica(CH₂Cl₂/MeOH, 29:1) gave the tertiary piperidine as a white foam (86.3mg, 59%). ¹H NMR (CDCl₃) δ 0.95 (d, 3H, J=6.2 Hz), 1.18-1.71 (m, 5H),1.84-1.97 (m, 1H), 2.09-2.20 (m, 1H), 2.40-2.50 (m, 1H), 2.63-2.83 (m,3H), 2.64-2.88 (m, 2H), 3.89 (s, 3H), 4.11 (s, 2H), 4.19-4.31 (m, 1H),4.36 (d, 2H, J=5.3 Hz), 4.69 (t, 1H, J=5.3 Hz), 6.92 (d, 1H, J=5.1 Hz),7.04 (s, 1H), 7.09 (d, 2H, J=8.4 Hz), 7.33 (dd, 1H, J=5.1, 3.1 Hz),7.57-7.63 (m, 2H), 7.75-7.81 (m, 2H), 7.90 (d, 2H, J=8.4 Hz).

A solution of the phthalimide (86.3 mg, 0.15 mmol) and hydrazine hydrate(0.10 ml, 1.8 mmol) in EtOH (1.5 ml) was stirred at room temperature for16 hours. The resulting suspension was diluted with saturated aqueousNaHCO₃ (25 ml) and extracted with CH₂Cl₂ (20 ml×4). The organic solutionwas dried (Na₂SO₄), filtered and concentrated under reduced pressure,giving the crude primary amine as a white foam (60.0 mg, 89%). ¹H NMR(CDCl₃) δ 0.94 (d, 3H, J=6.6 Hz), 1.32-1.68 (m, 6H), 1.71-1.79 (m, 2H),2.18-2.27 (m, 1H), 2.42-2.52 (m, 1H), 2.63-2.84 (m, 5H), 3.89 (s, 3H),4.32 (tt, 1H, J=11.9, 4.1 Hz), 4.37 (s, 2H), 4.40 (d, 2H, J=5.7 Hz),4.75 (t, 1H, J=5.8 Hz), 6.96 (d, 1H, J=4.8 Hz), 7.07 (dd, 1H, J=2.4, 1.2Hz), 7.14 (d, 2H, J=7.8 Hz), 7.32 (dd, 1H, J=4.8, 3.0 Hz), 7.92 (d, 2H,J=7.8 Hz).

A solution of the crude primary amine (60.0 mg, 0.13 mmol),6-chloro-2,4-dimethylnicotinic acid hydrochloride (36 mg, 0.16 mmol),EDCI (37 mg, 0.19 mmol), HOBT (29 mg, 0.21 mmol) and NMM (45 μL, 0.41mmol) in DMF (1.0 ml) was stirred at room temperature for 17.5 hours.The reaction was diluted with saturated aqueous NaHCO₃ (25 ml) and wasextracted with CH₂Cl₂ (20 ml×3). The combined organic solution was dried(Na₂SO₄), filtered and concentrated under reduced pressure. Purificationby flash column chromatography on silica (CH₂Cl₂/MeOH, 19:1, increasedto 9:1) gave COMPOUND 189 as a light yellow foam (49.0 mg, 60%). ¹H NMR(CDCl₃) δ 0.80-1.35 (m, 6H), 1.53-1.96 (m, 5H), 2.28 (s, 3H), 2.49 (s,3H), 2.60-3.04 (m, 4H), 3.26-3.41 (m, 1H), 3.72-3.95 (m, 2H), 3.90 (s,3H), 4.29-4.45 (m, 1H), 4.36 (d, 2H, J=5.3 Hz), 4.70-4.80 (m, 1H), 6.94(s, 1H), 7.01 (d, 1H, J=4.8 Hz), 7.09 (s, 1H), 7.11 (d, 2H, J=8.4 Hz),7.35 (dd, 1H, J=5.1, 2.8 Hz), 7.92 (d, 2H, J=8.4 Hz), 8.75 (br s, 1H);ES-MS m/z 626 (M+H), 628 (M+H+2).

Example 190

Compound 1906-Chloro-N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

To a solution of((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (104 mg, 0.28 mmol) in MeOH (5 ml) was addedmethyl trifluoroacetate (0.15 ml, 1.49 mmol) and the reaction stirred atrt overnight. The mixture was concentrated, diluted with CH₂Cl₂ (1.5 ml)and TFA (1.5 ml) and stirred for 1 h. The reaction was then concentratedand diluted with CH₂Cl₂ (10 ml) and 1 N NaOH (10 ml). The aqueous layerwas extracted with CH₂Cl₂ (2×10 ml) and the combined organic extractsdried (Na₂SO₄) and concentrated.

Following general procedure E: to a solution of the above crude productin DMF (2 ml) was added 6-chloro-2,4-dimethyl-nicotinic acid (64 mg,0.29 mmol), HOBt (47 mg, 0.35 mmol), DIPEA (0.25 ml, 1.44 mmol) and EDCI(68 mg, 0.35 mmol) and the reaction stirred overnight. Purification ofthe crude product by column chromatography on silica gel(CH₂Cl₂/MeOH/NH₄OH, 96:4:0 then 88:10:2) afforded the desired amide (72mg, 48% over 3 steps) as a pale yellow oil. To a solution of the amidefrom above (72 mg, 0.14 mmol) in MeOH (5 ml) was added K₂CO₃ (77 mg,0.56 mmol) and the reaction stirred at 60° C. for 2.5 h. The reactionwas then cooled, concentrated and diluted with CH₂Cl₂ (25 ml) andsaturated aqueous NaHCO₃ (20 ml). The aqueous layer was extracted withCH₂Cl₂ (2×10 ml) and the combined organic layers dried (Na₂SO₄) andconcentrated to afford the crude product as a yellow oil.

To a suspension of methoxylamine hydrochloride (157 mg, 1.88 mmol) inCH₃CN (5 ml) was added DIPEA (0.55 ml, 3.16 mmol) followed by CDI (302mg, 1.86 mmol) and the reaction stirred at rt for 1.5 h after which asolution of the amine from above (69 mg, 0.16 mmol) in CH₃CN (5 ml) wasadded and the reaction stirred at 60° C. overnight. The solution wascooled, treated with saturated aqueous NaHCO₃ (20 ml) and extracted withCH₂Cl₂ (3×15 ml). The combined organic extracts were dried (Na₂SO₄),filtered, and concentrated. Purification of the crude material by radialchromatography on silica gel (1 mm plate, CH₂Cl₂₁MeOH/NH₄OH, 96:4:0 then9:1:0 then 88:10:2) provided COMPOUND 190 (37 mg, 46%) as a white foam.¹H NMR (CDCl₃) δ 0.85-1.08 (m, 1H), 0.98 (d, 3H, J=6.6 Hz), 1.48-1.55(m, 1H), 1.65-1.77 (m, 4H), 2.14-2.21 (m, 1H), 2.27 (s, 3H), 2.48 (s,3H), 2.54-2.61 (m, 1H), 2.69-2.84 (m, 3H), 3.26-3.31 (m, 1H), 3.62 (s,3H), 3.63-3.69 (m, 2H), 3.71-3.85 (m, 1H), 4.19-4.24 (m, 1H), 6.93 (s,1H), 7.02-7.03 (m, 2H), 7.10-7.12 (m, 1H), 7.37 (dd, 1H, J=4.8, 3 Hz),8.75 (br d, 1H); ¹³C NMR (CDCl₃) δ 13.83, 19.12, 22.42, 30.03, 30.91,30.98, 40.50, 41.22, 43.61, 52.11, 52.57, 60.91, 64.66, 121.73, 122.82,126.39, 127.95, 133.22, 139.09, 147.93, 150.44, 155.74, 159.43, 167.40;ES-MS m/z 508 (M+H). Anal. Calcd. for C₂₄H₃₄N₅O₃SCl·0.7CH₂Cl₂: C, 52.27;H, 6.29; N, 12.34. Found: C, 52.18; H, 6.27; N, 12.34.

Examples 191 to 208 were prepared following the scheme illustratedbelow. R¹COOH is as defined in the table.

TABLE 15

Example R¹COOH 191 2,6-dichloro-4-methyl-nicotinic acid-N-oxide 1926-cyano-2,4-dimethyl-nicotinic acid 1932-chloro-6-cyano-4-methyl-nicotinic acid 1944-chloro-2,6-dimethyl-nicotinic acid 195 6-fluoro-2,4-dimethyl-nicotinicacid 196 2,4-dichloro-6-methyl-benzoic acid 1974-cyano-2,6-dimethyl-nicotinic acid-N-oxide 1984-chloro-2,6-dimethyl-nicotinic acid-N-oxide 1992-chloro-6-isopropylcarbamoyl-4-methyl- nicotinic acid 2002,6-dimethyl-4-[1,2,4]triazol-4-yl-benzoic acid (Schering patentPCT/US00/11632) 201 2,4-dimethyl-6-pyrimidin-5-yl-nicotinic acid 2022,6-dimethyl-4-pyridin-4-yl-benzoic acid 2032,6-dimethyl-4-thiophen-2-yl-benzoic acid 2046-cyclopropyl-2,4-dimethyl-nicotinic acid 2054-(3-propyl-ureido)-benzoic acid 2062,6-dimethyl-4-(3-isopropyl-ureido)-benzoic acid 2072,4-dimethyl-6-(3-methyl-pyrazol-1-yl)- nicotinic acid 2086-isobutyl-2,4-dimethyl-nicotinic acid

Example 191

Compound 1912,6-Dichloro-4-methyl-N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide-N-oxide

2,6-Dichloro-4-methyl-nicotinic acid (0.234 g, 1.14 mmol) and hydrogenperoxide-urea adduct (0.537 g, 5.70 mmol) were suspended in CH₂Cl₂ togive a white slurry. Trifluoroacetic anhydride (0.65 ml, 4.67 mmol) wasadded dropwise over 5 minutes and the resulting pale yellow solution wasstirred overnight at rt. The reaction mixture was quenched with water(10 ml) and then dry loaded onto silica gel and purified using columnchromatography (MeCN/MeOH/NH₄OH, 8:1:1, v/v/v) to give2,6-dichloro-4-methyl-nicotinic acid-N-oxide as a pale yellowcrystalline solid (0.103 g, 41%). ¹H NMR (CD₃OD) δ 2.37 (s, 3H), 7.60(s, 1H).

COMPOUND 191 was isolated as a white foam. ¹H NMR (CDCl₃) δ 0.99 (d, 3H,J=9.0 Hz), 1.25 (m, 1H), 1.37 (m, 1H), 1.56 (m, 2H), 1.74 (m, 3H), 2.22(br t, 1H), 2.31 (s, 3H), 2.57 (br t, 1H), 2.74-2.86 (m, 3H), 3.39 (m,1H), 3.63 (s, 1H), 3.70 (m, 1H), 3.98 (s, 2H), 4.16 (m, 1H), 6.98 (d,1H, J=6.0 Hz), 7.02 (s, 1H), 7.12 (s, 1H), 7.18 (s, 1H), 7.36 (m, 1H),8.57 (br t, 1H); ES-MS m/z 499 (M+H). Anal. Calcd. forC₂₃H₃₁N₅O₄Cl₂S·0.5H₂O: C, 49.91; H, 5.83; N, 12.65. Found: C, 49.82; H,5.68; N, 12.58.

Example 192

Compound 1926-Cyano-2,4-dimethyl-N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

¹H NMR (CDCl₃) δ 0.95-1.06 (d+m, 5H), 1.51 (m, 1H), 1.66-1.77 (m, 4H),2.20 (br t, 1H), 2.32 (s, 3H), 2.54 (s, 3H), 2.58 (br t, 1H), 2.70-2.85(m, 3H), 3.31 (m, 1H), 3.62 (s, 3H), 3.68 (s, 2H), 3.86 (m, 1H), 4.21(m, 1H), 7.00 (s, 2H), 7.14 (s, 1H), 7.21 (s, 1H), 7.41 (m, 1H), 8.75(br s, 1H); ES-MS m/z 499 (M+H).

Example 193

Compound 1932-Chloro-6-cyano-4-methyl-N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

To a suspension of 2-chloro-4-methyl-nicotinic acid (4.38 g, 25.6 mmol)in 1,2-dichloroethane (110 ml) at room temperature was added hydrogenperoxide-urea adduct (ground to a powder with mortar and pestle, 11.85g, 126.0 mmol) followed by trifluoroacetic anhydride (15.0 ml, 107.9mmol) dropwise over 5 minutes and the resulting suspension was stirredat 65° C. overnight. The mixture was concentrated, diluted with 1 N HCl(20 ml) and extracted with CH₂Cl₂/MeOH (4:1, 10×100 ml). The organicextracts were dried (Na₂SO₄), concentrated and purified by columnchromatography on silica gel (dry loaded, MeCN/MeOH/NH₄OH, 8:1:1) togive the desired N-oxide as a white solid (1.85 g, 39%). ¹H NMR (CD₃OD)δ 2.39 (s, 3H), 7.32 (d, 1H, J=6.6 Hz), 8.27 (d, 1H, J=6.6 Hz).

To a suspension of 2-chloro-4-methyl-1-oxy-nicotinic acid (1.85 g, 9.84mmol) in 1,2-dichloroethane/DMF (3:1, 40 ml) was added dimethylcarbamylchloride (1.8 ml, 19.6 mmol) followed by trimethylsilyl cyanide (3.0 ml,28.6 mmol) and the reaction stirred at 50° C. overnight. The mixture wasconcentrated, diluted with 1 N HCl (9 ml) and extracted with CH₂Cl₂/MeOH(9:1, 3×100 ml). The organic extracts were dried (Na₂SO₄), concentratedand purified by column chromatography (dry loaded, MeCN/MeOH/NH₄OH,8:1:1) to afford 2-chloro-6-cyano-4-methyl-nicotinic acid (0.83 g, 43%)as a brown solid. ¹H NMR (CD₃OD) δ 2.42 (s, 3H), 7.71 (s, 1H).

COMPOUND 193 was isolated as a white foam. ¹H NMR (CDCl₃) δ 0.98-1.08(m, 1H), 1.01 (d, 3H, J=6.6 Hz), 1.20-1.28 (m, 1H), 1.52-1.60 (m, 1H),1.69-1.78 (m, 3H), 2.14-2.22 (m, 1H), 2.39 (s, 3H), 2.52-2.60 (m, 1H),2.73-2.87 (m, 3H), 3.26-3.35 (m, 1H), 3.61 (s, 3H), 3.79-3.84 (m, 3H),4.09-4.13 (m, 1H), 6.96 (d, 1H, J=4.8 Hz), 6.99 (s, 1H), 7.12 (br s,1H), 7.33 (s, 1H), 7.41 (dd, 1H, J=4.8, 3 Hz), 8.83 (br d, 1H); ¹³C NMR(CDCl₃) δ 13.40, 19.09, 29.93, 30.51, 39.79, 41.44, 43.47, 51.38, 52.88,59.67, 64.10, 115.62, 121.44, 125.85, 127.71, 128.97, 132.21, 136.94,138.47, 148.62, 149.57, 158.85, 163.27; ES-MS m/z 541 (M+Na). Anal.Calcd. for C₂₄H₃₁N₆O₃SCl·0.2H₂O·0.2CH₂Cl₂: C, 53.86; H, 5.94; N, 15.57;Cl, 9.20; S, 5.94. Found: C, 53.79; H, 5.99; N, 15.69; Cl, 9.14; S,5.89.

Example 194

Compound 1942,6-Dichloro-N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-4-methyl-nicotinamide

¹H NMR (CDCl₃) δ 0.90-1.03 (m, 1H), 0.97 (d, 3H, J=6.6 Hz), 1.18-1.23(m, 1H), 1.49-1.54 (m, 1H), 1.68-1.75 (m, 3H), 2.12-2.20 (m, 1H), 2.31(s, 3H), 2.52-2.58 (m, 1H), 2.71-2.84 (m, 3H), 3.26-3.31 (m, 1H), 3.60(s, 3H), 3.75-3.80 (m, 1H), 3.80 (s, 2H), 4.13-4.18 (m, 1H), 6.97 (d,1H, J=4.8 Hz), 7.03-7.05 (m, 2H), 7.09 (s, 1H), 7.35 (dd, 1H, J=4.8, 3Hz), 8.74 (br d, 1H); ¹³C NMR (CDCl₃) δ 13.35, 18.99, 29.76, 30.40,30.48, 39.85, 40.88, 43.29, 51.39, 52.40, 59.86, 64.07, 121.25, 124.18,125.92, 127.33, 132.43, 138.67, 146.45, 149.63, 150.75, 158.90, 163.97;ES-MS m/z 528 (M+H). Anal. Calcd. for C₂₃H₃₁N₅O₃SCl₂·0.3CH₂Cl₂·0.4H₂O:C, 49.87; H, 5.82; N, 12.48; Cl, 16.43; S, 5.71. Found: C, 49.84; H,5.86; N, 12.16; Cl, 16.73; S, 5.62.

Example 195

Compound 1952,4-Dimethyl-6-fluoro-N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

¹H NMR (CDCl₃) δ 0.92 (m, 1H), 0.99 (d, 3H, J=6.0 Hz), 1.03 (m, 1H),1.54 (m, 1H), 1.68-1.77 (m, 4H), 2.18 (br t, 1H), 2.30 (s, 3H), 2.45 (s,3H), 2.60 (br t, 1H), 2.70 (m, 1H), 2.82 (m, 2H), 3.28 (m, 1H), 3.61 (s,3H), 3.67 (s, 2H), 3.84 (m, 1H), 4.24 (m, 1H), 6.43 (s, 1H), 6.95-6.99(s+m, 2H), 7.08 (s, 1H), 7.38 (m, 1H), 8.72 (br s, 1H); ES-MS m/z 492(M+H).

Example 196

Compound 1962,6-Dichloro-4-methyl-N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-benzamide

¹H NMR (CDCl₃) δ 0.98 (d+m, 4H), 1.13 (m, 1H), 1.50 (m, 1H), 1.68-1.75(m, 4H), 2.20 (br t, 1H), 2.30 (s, 3H), 2.56 (br t, 1H), 2.75-2.92 (m,3H), 3.28 (m, 1H), 3.61 (s, 3H), 3.69 (s, 2H), 3.82 (m, 1H), 4.24 (m,1H), 6.93 (d, 1H, J=3.0 Hz), 6.94 (s, 1H), 6.98 (s, 1H), 7.10 (m, 2H),7.38 (m, 1H), 8.72 (br s, 1H); ES-MS m/z 528 (M+H).

Example 197

Compound 1976-Cyano-2,4-dimethyl-N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide-N-oxide

¹H NMR (CDCl₃) δ 0.99 (d, 3H, J=9.0 Hz), 1.25 (m, 1H), 1.38 (m, 1H),1.55 (m, 1H), 1.73-1.81 (m, 4H), 2.23 (br t, 1H), 2.31 (s, 3H), 2.43 (s,3H), 2.59 (br t, 1H), 2.72-2.85 (m, 3H), 3.36 (m, 1H), 3.63 (s, 3H),3.76 (m, 1H), 3.98 (s, 2H), 4.11 (m, 1H), 6.98 (d, 1H, J=3.0 Hz), 7.02(s, 1H), 7.14 (s, 1H), 7.19 (s, 1H), 7.39 (m, 1H), 8.54 (br s, 1H);ES-MS m/z 515 (M+H).

Example 198

Compound 1986-Chloro-2,4-dimethyl-N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide-N-oxide

¹H NMR (CDCl₃) δ 1.01 (d, 3H, J=7.5 Hz), 1.26 (m, 1H), 1.39 (m, 1H),1.57 (m, 1H), 1.73-1.84 (m, 4H), 2.27 (s+m, 4H), 2.46 (s, 3H), 2.52 (brt, 1H), 2.74-2.84 (m, 3H), 3.36 (m, 1H), 3.63 (s, 3H), 3.68 (m, 1H),3.97 (s, 2H), 4.21 (m, 1H), 6.99 (d, 1H, J=3.0 Hz), 7.05 (s, 1H), 7.09(s, 1H), 7.12 (s, 1H), 7.37 (m, 1H), 8.55 (br s, 1H); ES-MS m/z 546(M+H).

Example 199

Compound 199 6-Chloro-4-methyl-pyridine-2,5-dicarboxylic acid2-isopropylamide5-({(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

2-Chloro-6-cyano-4-methyl-nicotinic acid (0.315 g, 1.61 mmol) inconcentrated HCl (8 ml) was heated at 100° C. for 45 minutes and thenall solvent was removed in vacuo to yield a pale yellow crystallinesolid. The crude solid, EDCI (0.339 g, 1.77 mmol) and HOBt (0.239 g,1.77 mmol) were combined in DMF (8 ml) to give a pale yellow solution.To this solution was added DIPEA (1.85 ml, 10.6 mmol) followed byisopropylamine (137 μL, 1.61 mmol) and the resulting mixture was stirredat 25° C. for 16 hours. The reaction mixture was quenched with water (3ml) and then dry loaded onto silica gel and purified using columnchromatography (MeCN/MeOH/NH₄OH, 8:1:1, v/v/v) to give2-chloro-6-isopropylcarbamoyl-4-methyl-nicotinic acid (0.195 g, 47%).

COMPOUND 199 was isolated as a white foam. ¹H NMR (CDCl₃) δ 1.00 (d+m,4H), 1.12 (m, 1H), 1.28 (d, 6H, J=6.0 Hz), 1.56 (m, 1H), 1.69-1.78 (m,3H), 2.19 (br t, 1H), 2.39 (s, 3H), 2.57 (br t, 1H), 2.74 (m, 1H), 2.87(m, 2H), 3.34 (m, 1H), 3.66 (s+m, 5H), 3.83 (m, 1H), 4.19-4.27 (m, 2H),6.94 (s+d, 2H), 7.09 (s, 1H), 7.36 (m, 1H), 7.57 (d, 1H, J=9.0 Hz), 7.95(s, 1H), 8.70 (br d, 1H); ES-MS m/z 579 (M+H).

Example 200

Compound 200N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-2,6-dimethyl-4-1,2,4-triazol-4-yl-benzamide

¹H NMR (CDCl₃) δ 1.02 (d, 3H, J=6.6 Hz), 1.18-1.23 (m, 1H), 1.54-1.73(m, 5H) 2.18-2.25 (m, 1H), 2.37 (s, 6H), 2.54-2.63 (m, 1H), 2.75-2.90(m, 3H), 3.28-3.39 (m, 1H), 3.58 (s, 3H), 3.65-3.81 (m, 3H), 4.12-4.20(m, 1H), 6.69 (d, 1H, J=4.8 Hz), 6.85 (br s, 1H), 6.89 (s, 2H), 7.06 (s,1H), 7.30 (dd, 1H, J=4.8, 3 Hz), 8.19 (br s, 1H), 8.35 (s, 2H); ¹³C NMR(CDCl₃) δ 13.89, 19.73, 30.33, 31.04, 31.55, 39.80, 41.43, 44.12, 51.91,53.06, 60.19, 64.58, 120.59, 122.10, 126.29, 128.13, 133.70, 137.56,139.04, 139.50, 141.30, 159.48, 168.64; ES-MS m/z 540 (M+H). Anal.Calcd. for C₂₇H₃₇N₇O₃S·1.3CH₂Cl₂·0.1H₂O: C, 52.14; H, 6.15; N, 15.04.Found: C, 52.14; H, 6.06; N, 14.76.

Example 201

Compound 201N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-2,4-dimethyl-6-pyrimidin-5-yl-nicotinamide

To a solution of 6-chloro-2,4-dimethyl-nicotinic acid ethyl ester (0.30g, 1.40 mmol) and 5-pyrimidine boronic acid (0.522 g, 4.21 mmol) inargon-degassed DME/2 M Na₂CO₃ (4:1, 12.5 ml) was added Pd(PPh₃)₄ (162mg, 0.14 mmol) and the mixture heated to 90° C. overnight. The reactionwas cooled, diluted with EtOAc (25 ml) and H₂O (15 ml). The aqueouslayer was extracted with EtOAc (2×10 ml) and the combined organicextracts were dried (Na₂SO₄), concentrated and purified by columnchromatography on silica gel (Hexanes/EtOAc, 3:2) to afford2,4-dimethyl-6-pyrimidin-5-yl-nicotinic acid ethyl ester (306 mg, 85%).¹H NMR (CDCl₃) δ 1.43 (t, 3H, J=6 Hz), 2.44 (s, 3H), 2.64 (s, 3H), 4.47(q, 2H, J=6 Hz), 7.44 (s, 1H), 9.26 (s, 1H), 9.32 (s, 2H).

A solution of the ester from above (306 mg, 1.19 mmol) in EtOH/2 N NaOH(1:2, mL) was heated to reflux for 3 d then cooled and acidified withconcentrated HCl to pH 3. The mixture was concentrated to dryness,diluted with CH₂Cl₂/MeOH (4:1, 20 ml), filtered and concentrated toafford the acid as a white solid. ¹H NMR (CD₃OD) δ 2.44 (s, 3H), 2.62(s, 3H), 7.68 (s, 1H), 9.17 (s, 1H), 9.35 (s, 2H).

¹H NMR (CDCl₃) δ 0.95-1.01 (m, 1H), 1.01 (d, 3H, J=6.6 Hz), 1.21-1.26(m, 1H), 1.54-1.80 (m, 4H), 2.20 (br t, 1H, J=11.4 Hz), 2.40 (s, 3H),2.55-2.62 (m, 1H), 2.62 (s, 3H), 2.73-2.88 (m, 3H), 3.29-3.37 (m, 1H),3.57 (s, 3H), 3.60 (s, 2H), 3.80-3.89 (m, 1H), 4.13-4.23 (m, 1H), 6.72(dd, 1H, J=5.1, 0.9 Hz), 6.85 (br s, 1H), 6.88 (s, 1H), 7.26-7.28 (m,1H), 7.31 (s, 1H), 8.44 (br s, 1H), 9.24 (s, 2H), 9.25 (s, 1H); ¹³C NMR(CDCl₃) δ 13.88, 19.49, 22.89, 30.28, 31.15, 31.35, 40.21, 41.14, 43.85,52.03, 52.91, 60.47, 64.56, 119.39, 121.98, 126.27, 128.00, 132.04,134.04, 138.99, 145.67, 151.12, 155.33, 155.71, 159.05, 159.46, 168.05;ES-MS m/z 552 (M+H). Anal. Calcd. for C₂₈H₃₇N₇O₃S·1.2H₂O: C, 58.66; H,6.93; N, 17.10. Found: C, 58.75; H, 7.07; N, 16.99.

Example 202

Compound 202N—{(R)-3-[4-(3-methoxyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-2,6-dimethyl-4-pyridin-4-yl-benzamide

¹H NMR (CDCl₃) δ 0.97-1.05 (m, 4H), 1.54-1.70 (m, 5H), 2.18-2.25 (m,1H), 2.38 (s, 6H), 2.54-2.63 (m, 1H), 2.75-2.95 (m, 3H), 3.26-3.37 (m,1H), 3.47-3.58 (m, 2H), 3.57 (s, 3H), 3.76-3.85 (m, 1H), 4.11-4.25 (m,1H), 6.56-6.75 (m, 2H), 6.86-6.94 (m, 1H), 7.20 (s, 2H), 7.22-7.27 (m,1H), 7.41 (d, 2H, J=6 Hz), 8.45 (br s, 1H), 8.65 (d, 2H, J=6 Hz); ¹³CNMR (CDCl₃) δ 13.34, 19.25, 29.48, 30.33, 30.89, 39.36, 40.54, 43.50,51.52, 52.11, 60.17, 64.07, 121.31, 121.53, 125.83, 127.28, 135.10,137.75, 138.57, 147.39, 150.24, 159.03, 169.25; ES-MS m/z 550 (M+H).Anal. Calcd. for C₃₀H₃₉N₅O₃S·0.1CH₂Cl₂·1.3CH₃OH: C, 62.87; H, 7.46; N,11.67. Found: C, 62.96; H, 7.19; N, 11.33.

Example 203

Compound 203N—{(R)-3-[4-(3-methoxyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-2,6-dimethyl-4-thiophen-2-yl-benzamide

To a solution of 2,6-dimethyl-4-trifluoromethanesulfonyloxy-benzoic acidtert-butyl ester (prepared as described by patent Schering Corporation,WO 2000/66558 A1) (215 mg, 0.61 mmol) and 2-thiophene boronic acid (80mg, 0.625 mmol) in argon-degassed THF/DME/2 M Na₂CO₃ (1:1:1, 4.5 ml) wasadded Pd(PPh₃)₄ (35 mg, 0.030 mmol) and the mixture heated to 90° C.overnight. The reaction was cooled, diluted with EtOAc (25 ml) and H₂O(15 ml). The aqueous layer was extracted with EtOAc (2×10 ml) and thecombined organic extracts were dried (Na₂SO₄), concentrated and purifiedby column chromatography on silica gel (Hexanes/EtOAc, 92:8) to affordthe desired coupled product (88 mg, 50%) as a clear oil. ¹H NMR (CDCl₃)δ 1.61 (s, 9H), 2.37 (s, 6H), 7.07 (dd, 1H, J=5.1, 3.6 Hz), 7.27-7.30(m, 2H). ES-MS m/z 311 (M+Na).

A solution of the t-butyl ester from above (42 mg, 0.15 mmol) inCH₂Cl₂/TFA (1:6, 3.5 ml) was stirred overnight and concentrated toafford 2,6-dimethyl-4-thiophen-2-yl-benzoic acid as a white solid.

¹H NMR (CDCl₃) δ 0.91-0.99 (m, 1H), 0.98 (d, 3H, J=6.6 Hz), 1.08-1.14(m, 1H), 1.43-1.78 (m, 4H), 2.17 (br t, 1H, J=11.4 Hz), 2.32 (s, 6H),2.58 (dt, 1H, J=11.4, 1.8 Hz), 2.70-2.87 (m, 3H), 3.21-3.30 (m, 1H),3.44-3.51 (m, 2H), 3.56 (s, 3H), 3.88-3.93 (m, 1H), 4.14-4.22 (m, 1H),6.60 (dd, 1H, J=5.1, 1.2 Hz), 6.64-6.67 (m, 1H), 6.84 (s, 1H), 7.10 (dd,1H, J=4.8, 3.6 Hz), 7.17 (s, 2H), 7.23-7.26 (m, 2H), 7.31 (dd, 1H,J=4.8, 1.2 Hz), 8.72 (br d, 1H); ES-MS m/z 555 (M+H).

Example 204

Compound 2046-Cyclopropyl-N—{(R)-3-[4-(3-ethyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

General Procedure for Preparation of6-Substituted-2,4-dimethyl-nicotinic Acids:

To a solution of ethyl 2,4-dimethylpyridine-3-carboxylate (0.59 g, 3.29mmol) and cyclopropane carboxylic acid (1.2 ml (15.1 mmol) in 10%aqueous H₂SO₄ (3 ml) was added AgNO₃ (154 mg, 0.91 mmol) followed by asolution of ammonium persulfate (1:541 g, 6.75 mmol) in water (6 ml) andthe mixture stirred at room temperature overnight. The reaction wasneutralized to pH 10 with saturated aqueous NH₄OH (5 ml) and extractedwith EtOAc (3×20 ml). The combined organic extracts were dried (Na₂SO₄),concentrated and purified by column chromatography on silica gel(Hexanes/EtOAc, 96:4 then 1:1 then 0:100) to afford desired6-cyclopropyl-2,4-dimethyl-nicotinic acid ethyl ester (133 mg, 18%) as aclear oil along with recovered starting ethyl2,4-dimethylpyridine-3-carboxylate (0.31 g). ¹H NMR (CDCl₃) δ 0.93-0.97(m, 4H), 1.38 (t, 3H, J=6 Hz), 1.92-2.02 (m, 1H), 2.28 (s, 3H), 2.47 (s,3H), 4.39 (q, 2H, J=6 Hz), 6.73 (s, 1H).

A solution of the ester from above (133 mg, 0.61 mmol) in EtOH/10 N NaOH(1:1, 3 ml) was heated to reflux for 3 h then cooled and acidified withconcentrated HCl (1.5 ml). The mixture was concentrated to dryness,diluted with CH₂C₂/MeOH (1:1, 30 ml), filtered and concentrated toafford 6-cyclopropyl-2,4-dimethyl-nicotinic acid (15 mg, 99%) as a whitesolid. ¹H NMR (CD₃OD) δ 1.26-1.31 (m, 2H), 1.46-1.52 (m, 2H), 2.39-2.44(m, 1H), 2.63 (s, 3H), 2.82 (s, 3H), 7.39 (s, 1H).

¹H NMR (CDCl₃) δ 0.89-0.99 (m, 8H), 1.49-1.76 (m, 5H), 1.87-1.93 (m,1H), 2.14-2.23 (m, 1H), 2.23 (s, 3H), 2.44 (s, 3H), 2.52-2.60 (m, 1H),2.70-2.87 (m, 3H), 3.22-3.31 (m, 1H), 3.63 (s, 3H), 3.64-3.82 (m, 3H),4.13-4.21 (m, 1H), 6.63 (s, 1H), 6.98 (d, 1H, J=4.8 Hz), 7.05 (s, 1H),7.08 (br s, 1H), 7.35 (dd, 1H, J=4.8, 3 Hz), 8.32 (br s, 1H); ¹³C NMR(CDCl₃) δ 8.99, 9.03, 12.68, 16.38, 18.07, 21.68, 28.54, 29.49, 30.29,38.81, 40.25, 42.83, 50.89, 51.44, 59.56, 63.56, 118.48, 120.66, 125.48,126.66, 129.97, 138.37, 142.85, 152.84, 158.43, 161.39, 168.17; ES-MSm/z 514 (M+H). Anal. Calcd. for C₂₇H₃₉N₅O₃S·0.9CH₂Cl₂: C, 56.78; H,6.97; N, 11.87. Found: C, 57.04; H, 7.01; N, 11.62.

Example 205

Compound 2052,6-Dimethyl-N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-4-(3-propyl-ureido)-benzamide

To a solution of 3,5-dimethylaniline (3.0 ml, 24 mmol) in ice colddichloromethane (200 ml) was added trifluoroacetic anhydride (4.18 mL,1.25 equivs). After 30 minutes, bromine (1.2 ml, 0.97 equivs) was slowlyadded over 5 minutes. After aqueous work-up and drying in vacuo therecovered crude (6.81 g, 96%) was taken up in dry THF (40 ml). Thesolution was cooled to −78° C. and methyl lithium lithium bromidecomplex (21 ml, 1.3 equivs) was added. After 5 minutes, s-butyllithium(20 ml, 1.3 equivs) was added followed by di-t-butyldicarbonate (8.02 g,1.6 equivs). Following aqueous work up the crude amide was taken up in a3:1 solution of methanol:water (100 ml) followed by sodium hydroxide (5ml, 10M, 2 equivs). The reaction was stirred at 60° C. overnight.Solvent was removed and the crude was diluted with dichloromethane,washed with water, brine, and dried over sodium sulfate. The aniline wasthen taken up in dichloromethane (2 ml) and n-propylisocyanate (74 μL,1.2 equivs). After two hours, solvent was removed and the crude residuewas taken up in HCl/ethanol solution (1.2M, 15 ml) and stirred at 50° C.overnight. After solvent was removed, the crude2,6-dimethyl-4-(3-propyl-ureido)-benzoic acid was isolated as a whitesolid (94 mg).

¹H NMR (CDCl₃) δ 0.83-0.99 (m, 7H), 1.02-1.11 (m, 1H), 1.46-1.77 (m,8H), 2.11 (s, 6H), 2.48-2.57 (m, 1H), 1.66-1.82 (m, 3H), 3.12-3.22 (m,3H), 3.52-3.20 (m, 4H), 3.75-3.82-3.90 (m, 1H), 4.11-4.25 (m, 1H),5.67-5.75 (m, 1H), 6.61 (s, 2H), 6.89 (d, 1H, J=6 Hz), 7.03 (s, 1H),7.22 (s, 1H), 7.27-7.32 (m, 1H), 7.48 (s, 1H), 8.87 (br s, 1H); ES-MSm/z 573 (M+H).

Example 206

Compound 2064-(3-Isopropyl-ureido)-2,6-dimethyl-N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-benzamide

2,6-Dimethyl-4-(3-isopropyl-ureido)-benzoic acid was prepared in thesame manner as 2,6-dimethyl-4-(3-propyl-ureido)-benzoic acid (seeEXAMPLE 205) except isopropyl isocyanate was used in lieu ofn-propylisocyanate.

¹H NMR (CDCl₃) δ 0.82-0.89 (m, 1H), 0.97 (d, 3H, J=6 Hz), 1.07-1.21 (m,1H), 1.18 (d, 6H, J=6 Hz), 1.47-1.55 (m, 1H), 1.57-1.63 (m, 4H),1.65-1.76 (m, 2H), 2.14 (s, 6H), 2.55-2.61 (m, 1H), 2.67-2.81 (m, 3H),3.18-3.26 (m, 1H), 3.53-3.62 (m, 3H), 3.81-3.87 (m, 1H), 3.87-3.98 (m,1H), 4.22-4.24 (m, 1H), 5.30 (d, 1H, J=6 Hz), 6.62 (s, 2H), 6.89 (d, 1H,J=3 Hz), 7.05 (br s, 2H), 7.16 (s, 1H), 7.29-7.33 (m, 1H), 8.85 (br s,1H); ES-MS m/z 595 (M+Na).

Example 207

Compound 207N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-2,4-dimethyl-6-(3-methyl-pyrazol-1-yl)-nicotinamide

To a solution of 3-methylpyrazole (156 mg, 1.90 mmol) in DMF (2 ml) wasadded NaH (60% dispersion in oil, 76 mg, 1.9 mmol) and the reactionstirred at room temperature for 30 min. before adding2-chloro-5-bromo-4,6-dimethylpyridine (227 mg, 1.03 mmol) as a solid inone portion. The mixture was heated to 85° C. for 2 d then cooled anddiluted with EtOAc (35 ml) and brine (20 ml). The organic layer waswashed with brine (2×15 ml) and water (1×10 ml), dried (Na₂SO₄),concentrated and purified by column chromatography on silica gel(Hexanes/Et₂O, 9:1) to afford3-bromo-2,4-dimethyl-6-(3-methyl-pyrazol-1-yl)-pyridine (172 mg, 63%) asa white crystalline solid. ¹H NMR (CDCl₃) δ 2.36 (s, 3H), 2.44 (s, 3H),2.65 (s, 3H), 6.23 (d, 1H, J=3 Hz), 7.62 (s, 1H), 8.41 (d, 1H, J=3 Hz).

To a solution of 3-bromo-2,4-dimethyl-6-(3-methyl-pyrazol-1-yl)-pyridine(172 mg, 0.65 mmol) in anhydrous Et₂O (10 ml) at −78° C. was added asolution of t-BuLi (1.7 M in pentane, 0.76 ml, 1.29 mmol) and thereaction stirred at −78° C. for 20 min. Carbon dioxide (dry ice) wasthen bubbled into the resultant orange suspension at −78° C. for 15 min.and the reaction was warmed to room temperature and stirred for 30 min.The mixture was diluted with water (7 ml) and Et₂O (10 ml) and thelayers separated. The aqueous layer was acidified with concentrated HClto pH 2-3 and concentrated. The resultant solid was diluted withCH₂Cl₂/MeOH (5:1, 30 ml), filtered, concentrated and purified by columnchromatography on silica gel (CH₃CN/MeOH/NH₄OH, 95:5:0 then 7:2:1) toafford 2,4-dimethyl-6-(3-methyl-pyrazol-1-yl)-nicotinic acid (100 mg,67%) as a white solid. ¹H NMR (CD₃OD) δ 2.39 (s, 3H), 2.49 (s, 3H), 2.58(s, 3H), 6.37 (d, 1H, J=3 Hz), 7.61 (s, 1H), 8.51 (d, 1H, J=3 Hz).

¹H NMR (CDCl₃) δ 0.89-1.10 (m, 2H), 0.98 (d, 3H, J=6.6 Hz), 1.49-1.72(m, 4H), 2.17 (br t, 1H, J=11.4 Hz), 2.34 (s, 3H), 2.39 (s, 3H), 2.50(s, 3H), 2.57 (br t, 1H, J=11.4 Hz), 2.71-2.86 (m, 3H), 3.23-3.31 (m,1H), 3.50 (br s, 2H), 3.57 (s, 3H), 3.82-3.89 (m, 1H), 4.14-4.24 (m,1H), 6.26 (d, 1H, J=2.4 Hz), 6.77 (d, 1H, J=5.1 Hz), 6.86 (br s, 1H),6.88 (s, 1H), 7.28 (dd, 1H, J=5.1, 3 Hz), 7.54 (s, 1H), 8.42 (d, 1H,J=2.4 Hz), 8.70 (br s, 1H); ¹³C NMR (CDCl₃) δ 13.82, 14.31, 19.52,22.58, 29.94, 31.02, 40.50, 41.08, 43.60, 52.15, 52.57, 61.00, 64.59,108.48, 110.39, 121.56, 126.24, 127.69, 128.31, 131.66, 139.05, 147.53,150.63, 152.18, 153.92, 159.38, 168.30; ES-MS m/z 576 (M+Na). Anal.Calcd. for C₂₈H₃₉N₇O₃S·0.3CH₂Cl₂·0.2H₂O: C, 58.32; H, 6.92; N, 16.82.Found: C, 58.48; H, 6.97 N, 16.46.

Example 208

Compound 208N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-6-isobutyl-2,4-dimethyl-nicotinamide

6-Isobutyl-2,4-dimethyl-nicotinic acid was prepared using GeneralProcedure for Preparation of 6-Substituted-2,4-dimethyl-nicotinic Acids(see EXAMPLE 204).

¹H NMR (CDCl₃) δ 0.87-0.91 (m, 1H), 0.89 (d, 6H, J=6.6 Hz), 0.99 (d, 3H,J=6.6 Hz), 1.01-1.20 (m, 1H), 1.49-1.74 (m, 5H), 1.97-2.06 (m, 1H),2.16-2.24 (m, 1H), 2.26 (s, 3H), 2.48 (d, 2H, J=7.5 Hz), 2.49 (s, 3H),2.70-2.87 (m, 3H), 3.26-3.34 (m, 1H), 3.61 (s, 3H), 3.74-3.82 (m, 3H),4.13-4.19 (m, 1H), 6.70 (s, 1H), 6.94 (dd, 1H, J=4.8, 0.9 Hz), 7.05-7.07(m, 2H), 7.35 (dd, 1H, J=4.8, 3 Hz), 8.17 (br s, 1H); ¹³C NMR (CDCl₃) δ13.30, 18.64, 22.18, 22.27, 28.97, 29.49, 30.41, 30.97, 39.46, 40.79,43.36, 47.22, 51.44, 52.35, 59.81, 64.05, 121.22, 121.95, 126.01,127.25, 131.00, 138.94, 143.61, 153.37, 158.95, 160.65, 168.61; ES-MSm/z 530 (M+H). Anal. Calcd. for C₂₈H₄₃N₅O₃S·0.2CH₂Cl₂·0.2H₂O: C, 61.55;H, 8.02; N, 12.73. Found: C, 61.45; H, 8.03; N, 12.69.

Example 209

Compound 209 4,6-Dimethyl-[2,3′]bipyridinyl-5-carboxylic acid{(R)-3-[4-(3-methoxyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide

To an argon-degassed solution of6-chloro-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(100 mg, 0.23 mmol) and 3-pyridine boronic acid (56 mg, 0.46 mmol) inDME/2 M Na₂CO₃ (5:2, 3.5 ml) was added Pd(PPh₃)₄ (15 mg, 0.013 mmol) andthe reaction stirred at 90° C. overnight. The mixture was cooled,diluted with CH₂Cl₂ (25 ml) and saturated aqueous NaHCO₃ (25 ml). Theaqueous layer was extracted with CH₂Cl₂ (2×10 ml) and the combinedorganic extracts were dried (Na₂SO₄), concentrated and purified bycolumn chromatography on silica gel (CH₂Cl₂MeOH/NH₄OH, 96:4:0 then88:10:2) to afford 4,6-dimethyl-[2,3′]bipyridinyl-5-carboxylic acid((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide asa mixture of product and starting amine (˜25%).

To a solution of the mixture from above (100 mg) in CH₂Cl₂ (5 ml) wasadded DIPEA (0.10 ml, 0.58 mmol) andN-(4-nitrophenoxycarbonyl)methoxylamine (58 mg, 0.27 mmol) and thereaction stirred at room temperature for 1.5 h. The mixture was dilutedwith CH₂Cl₂ (25 ml) and 1 N NaOH (20 ml) and the aqueous layer wasextracted with CH₂Cl₂ (2×10 ml), dried (Na₂SO₄), concentrated andpurified by column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH,96:4:0 then 9:1:0 then 88:10:2) followed by preparative thin layerchromatography on silica gel (1 mm plate, CH₂C₂/MeOH/NH₄OH, 9:1) toafford COMPOUND 209 (70 mg, 55% 2 steps) as a white solid. ¹H NMR(CDCl₃) δ 1.01-1.09 (m, 4H), 1.44-1.72 (m, 5H), 2.28-2.37 (m, 1H), 2.37(s, 3H), 2.60 (s, 3H), 2.60-2.94 (m, 4H), 3.39-3.46 (m, 1H), 3.57 (s,3H), 3.61-3.76 (m, 3H), 4.20-4.30 (m, 1H), 6.73-6.77 (m, 1H), 6.82-6.87(m, 1H), 7.01-7.05 (m, 1H), 7.26-7.28 (m, 1H), 7.32 (s, 1H), 7.39 (dd,1H, J=7.8, 4.8 Hz), 8.27 (td, 1H, J=7.8, 2.1 Hz), 8.63 (d, 1H, J=4.8Hz), 9.11 (br s, 1H); ¹³C NMR (CDCl₃) δ 13.28, 19.07, 22.50, 29.03,29.96, 30.99, 39.00, 40.80, 43.81, 51.32, 51.86, 59.89, 64.10, 119.09,121.33, 123.54, 125.90, 127.30, 132.70, 134.28, 138.61, 144.84, 148.01,149.85, 153.48, 154.70, 159.00; ES-MS m/z 573 (M+Na). Anal. Calcd. forC₂₉H₃₈N₆O₃S·1.1CH₂Cl₂: C, 56.13; H. 6.29; N, 13.05. Found: C, 56.17; H,6.39; N, 12.94.

Examples 210 to 226 were prepared following the scheme illustratedbelow. R¹R²NH is as defined in the table and X is CH or N as shown inthe individual examples.

TABLE 16

Example R¹R²NH 210 Isopropylamine 211 Cyclopropylamine 212Isopropylamine 213 1,1-Dimethylhydrazine 214 N-Ethylmethylamine 215N-Methylallylamine 216 Morpholine 217 2-Methoxyethylamine 218 Ethylamine219 tert-Butylamine 220 Aminoacetonitrile hydrochloride 221(±)-sec-Butylamine 222 Isobutylamine 223 Allylamine 224 Pyrrolidine 225N-Methylisopropylamine 226 N-Methyl-tert-butylamine

Example 210

Compound 210 4,6-Dimethyl-pyridine-2,5-dicarboxylic acid2-isopropylamide5-({(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

1-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-3-methoxy-1-thiophen-3-ylmethyl-urea(0.150 g, 0.44 mmol), EDCI (0.093 g, 0.48 mmol) and HOBt (0.066 g, 0.48mmol) were combined in DMF (8 ml) to give a pale yellow solution. Tothis solution was added 6-cyano-2,4-dimethyl-nicotinic acid (0.091 g,0.48 mmol) followed by DIPEA (126 μL, 0.66 mmol) and the resultingmixture was stirred at 25° C. for 16 h. Standard workup according togeneral procedure E gave the crude product as a tan oil. Purification bycolumn chromatography on silica gel (Et₂O:MeOH:NH₄OH, 90:8:2, v/v/v)afforded6-cyano-2,4-dimethyl-N-{3-[4-(3-methyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide(0.170 g, 77%) as a white foam. ¹H NMR (CDCl₃) δ 0.95 (m, 1H), 1.03(d+m, 4H), 1.48 (m, 1H), 1.56-1.73 (m, 5H), 2.22 (br t, 1H), 2.32 (s,3H), 2.54 (s, 3H), 2.58 (br t, 1H), 2.71-2.85 (m, 3H), 3.31 (m, 1H),3.62 (s, 1H), 3.66 (m, 1H), 3.75 (s, 2H), 3.86 (m, 1H), 4.21 (m, 1H),7.00 (m, 2H), 7.14 (s, 1H), 7.21 (s, 1H), 7.41 (m, 1H), 8.75 (br d, 1H);ES-MS m/z 499 (M+H).

To a solution of6-cyano-2,4-dimethyl-N-{3-[4-(3-methyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide(0.150 g, 0.30 mmol) in ethanol (5 ml) was added 10 N NaOH (1 ml) andthe resulting colorless solution was stirred for 16 h at 100° C. Thereaction mixture was dry loaded onto silica gel and purified usingcolumn chromatography (MeCN:MeOH:NH₄OH, 6:3:1, v/v/v) to give4,6-dimethyl-5-{3-[4-(3-methyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butylcarbamoyl}-pyridine-2-carboxylicacid as a glassy white solid (0.117 g, 75%). ¹H NMR (CD₃OD)) δ 1.31 (d,3H, J=7.5 Hz), 1.86 (m, 4H), 2.03 (m, 3H), 2.31 (s, 3H), 2.43 (s, 3H),2.86 (m, 1H), 3.06 (m, 2H), 3.23 (m, 1H), 3.52 (m, 2H), 3.64 (s, 3H),4.09 (m, 1H), 4.38 (s, 2H), 6.98 (d, 1H, J=4.5 Hz), 7.17 (s, 1H), 7.32(m, 1H), 7.61 (s, 1H).

COMPOUND 210 was isolated as a white foam. ¹H NMR (CDCl₃) δ 0.84 (m,1H), 0.97 (d+m, 4H), 1.29 (d, 6H, J=6.0 Hz), 1.53 (m, 1H), 1.72 (m, 3H),2.17 (br t, 1H), 2.33 (s, 3H), 2.55 (s, 3H), 2.56 (br t, 1H), 2.68 (m,1H), 2.82 (m, 2H), 3.29 (m, 1H), 3.48-3.52 (m, 2H), 3.60 (s, 3H), 3.86(m, 1H), 4.22 (s, 2H), 4.29 (m, 1H), 6.95 (s, 1H), 6.97 (d, 1H, J=3.0Hz), 7.09 (s, 1H), 7.36 (m, 1H), 7.85 (s, 1H), 7.86 (d, 1H, J=6.0 Hz),8.64 (br d, 1H); ES-MS m/z 559 (M+H). Anal. Calcd. forC₂₈H₄₂N₆O₄S·0.9H₂O: C, 58.49; H, 7.68; N, 14.62. Found: C, 58.53; H,7.44; N, 14.35.

Example 211

Compound 211 4,6-Dimethyl-pyridine-2,5-dicarboxylic acid2-cyclopropylamide5-({(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

¹H NMR (CDCl₃) δ 0.66 (m, 2H), 0.86 (m, 3H), 0.98 (d+m, 4H), 1.55 (m,1H), 1.65-1.72 (m, 4H), 2.17 (br t, 1H), 2.33 (s, 3H), 2.52 (s, 3H),2.56 (br t, 1H), 2.69 (m, 1H), 2.82 (m, 2H), 2.93 (m, 1H), 3.29 (m, 1H),3.49 (m, 2H), 3.60 (s, 3H), 3.88 (m, 1H), 4.19 (m, 1H), 6.97 (s+d, 2H),7.10 (s, 1H), 7.36 (m, 1H), 7.83 (s, 1H), 8.01 (s, 1H), 8.71 (br s, 1H);ES-MS m/z 557 (M+H).

Example 212

Compound 212N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-N′-isopropyl-2,6-dimethyl-terephthalamide

Following general procedure E:1-[1-((R)-3-Amino-1-methyl-propyl)-piperidin-4-yl]-3-methoxy-1-thiophen-3-ylmethyl-urea(160 mg, 0.47 mmol), 4-cyano-2,6-dimethyl-benzoic acid (91 mg, 0.52mmol), EDCI (99 mg, 0.52 mmol), HOBt (70 mg, 0.52 mmol), DIPEA (0.12 ml,0.71 mmol), and DMF (5 ml) were combined and stirred at room temperatureovernight. The crude product was purified by flash chromatography(CH₂Cl₂, 8% MeOH) to afford the product (175 mg, 75%) as a white solid.

To a solution of4-cyano-N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-2,6-dimethyl-benzamide(175 mg, 0.35 mmol) in anhydrous alcohol (5 ml) was added 10N NaOH (1ml). The mixture was stirred at 100° C. overnight, concentrated, thendry-loaded onto a column. The crude product was purified with 7:2:1acetonitrile/methanol/NH₄OH to afford the product (162 mg, 89%) as awhite solid and possibly as a mixture of an amide and carboxylic acid.

COMPOUND 212 was isolated as a white solid. ¹H NMR (CDCl₃) δ 0.58-1.12(m, 2H), 0.98 (d, 3H, J=6.6 Hz), 1.28 (d, 6H, J=6.3 Hz), 1.44-1.58 (m,1H), 1.63-1.87 (m, 3H), 2.11-2.48 (m, 1H), 2.31 (s, 6H), 2.52-2.64 (m,1H), 2.72-2.76 (m, 1H), 2.77-2.93 (m, 2H), 3.26-3.32 (m, 1H), 3.49-3.50(m, 2H), 3.59 (s, 3H), 3.81-3.97 (m, 1H), 4.13-4.38 (m, 2H), 5.87 (d,1H, J=9 Hz), 6.96 (s, 1H), 6.98-6.99 (m, 1H), 7.11-7.12 (m, 1H), 7.30(s, 2H), 7.31-7.37 (m, 1H), 8.77 (d, 1H, J=6 Hz); ¹³C NMR (CDCl₃) δ13.46, 14.52, 19.19, 22.84, 29.17, 30.11, 31.08, 39.54, 40.61, 40.95,42.06, 43.66, 51.59, 51.85, 53.54, 60.53, 61.31, 64.29, 121.60, 126.02,126.28, 127.37, 134.61, 135.1, 138.94, 141.07, 159.14, 166.58, 169.22;ES-MS m/z 580 (M+Na).

Example 213

Compound 2136-(N′,N′-Dimethyl-hydrazinocarbonyl)-2,4-dimethyl-N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

¹H NMR (CDCl₃) δ 0.84 (m, 1H), 0.99 (d+m, 4H), 1.57 (m, 1H), 1.69 (m,3H), 2.17 (br t, 1H), 2.32 (s, 3H), 2.55 (s+br t, 4H), 2.72 (s, 7H),2.82 (m, 2H), 3.30 (m, 1H), 3.60 (s+m, 4H), 3.86 (m, 1H), 4.22 (m, 1H),6.98 (m, 2H), 7.11 (s, 1H), 7.35 (m, 1H), 7.86 (s, 1H), 8.62 (br s, 2H);ES-MS m/z 560 (M+H).

Example 214

Compound 214 4,6-Dimethyl-pyridine-2,5-dicarboxylic acid2-(ethyl-methyl-amide)5-({(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

¹H NMR (CDCl₃) (mixture of rotamers) δ 0.84 (m, 1H), 0.99 (d+m, 4H),1.13 (t, J=6.0 Hz) and 1.25 (t, J=6.0 Hz) (total 3H), 1.56 (m, 1H), 1.69(m, 3H), 2.17 (br t, 1H), 2.31 (s, 3H), 2.54 (s+br t, 4H), 2.72 (m, 1H),2.82 (m, 2H), 2.96 (s) and 3.08 (s) (total 3H), 3.30 (m, 2H), 3.61 (s+m,5H), 3.73 (m, 1H), 3.88 (m, 1H), 4.25 (m, 1H), 7.06 (d, J=3.0 Hz), 7.09(s, 1H), 7.18 (m, 2H), 7.31 (m, 1H), 8.83 (br s, 1H); ES-MS m/z 559(M+H).

Example 215

Compound 215 4,6-Dimethyl-pyridine-2,5-dicarboxylic acid2-(allyl-methyl-amide)5-({(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

¹H NMR (CDCl₃) (mixture of rotamers) δ 0.85 (m, 1H), 0.98 (d+m, 4H),1.55 (m, 1H), 1.65-1.76 (m, 3H), 2.17 (br t, 1H), 2.31 (s, 3H), 2.53(s+br t, 4H), 2.68 (m, 1H), 2.82 (m, 2H), 2.95 (s) and 3.07 (s) (total3H), 3.28 (m, 2H), 3.61 (s+m, 5H), 3.74 (m, 1H), 3.91 (m, 1H), 4.15-4.24(m, 1H), 5.13-5.31 (m, 2H), 5.78 (m, 1H), 7.06 (d, 1H, J=3.0 Hz), 7.14(m, 2H), 7.21 (s, 1H), 7.31 (m, 1H), 8.82 (br s, 1H); ES-MS m/z 571(M+H).

Example 216

Compound 2162,4-Dimethyl-6-(morpholine-4-carbonyl)-N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

¹H NMR (CDCl₃) δ 0.85 (m, 1H), 0.98 (d+m, 4H), 1.55 (m, 1H), 1.66-1.73(m, 3H), 2.17 (br t, 1H), 2.32 (s, 3H), 2.53 (s, 3H), 2.57 (br t, 1H),2.68 (m, 1H), 2.83 (m, 2H), 3.26 (m, 1H), 3.55 (m, 2H), 3.61 (s, 3H),3.69 (m, 4H), 3.75 (s, 3H), 3.87 (m, 1H), 4.23 (m, 1H), 7.06 (d, 1H,J=3.0 Hz), 7.14 (m, 2H), 7.32 (m, 1H), 8.82 (br d, 1H); ES-MS m/z 587(M+H).

Example 217

Compound 217 4,6-Dimethyl-pyridine-2,5-dicarboxylic acid2-[(2-methoxy-ethyl)-amide]5-({(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

¹H NMR (CDCl₃) δ 0.81 (m, 1H), 0.98 (d+m, 4H), 1.54 (m, 1H), 1.63-1.75(m, 4H), 2.16 (br t, 1H), 2.34 (s, 3H), 2.52 (s+br t, 4H), 2.67 (m, 1H),2.82 (m, 2H), 3.28 (m, 1H), 3.34 (s, 3H), 3.56 (m, 3H), 3.61 (s, 3H),3.67 (m, 1H), 3.87 (m, 1H), 4.20 (m, 1H), 6.96 (d, 1H, J=6.0 Hz), 7.07(s, 1H), 7.16 (s, 1H), 7.34 (m, 1H), 7.86 (s, 1H), 8.25 (br t, 1H), 8.75(br d, 1H); ES-MS m/z 575 (M+H).

Example 218

Compound 218 4,6-Dimethyl-pyridine-2,5-dicarboxylic acid 2-ethylamide5-({(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

¹H NMR (CDCl₃) δ 0.83 (m, 1H), 0.98 (d+m, 4H), 1.26 (t, 3H, J=6.0 Hz),1.54 (m, 1H), 1.64-1.75 (m, 4H), 2.17 (br t, 1H), 2.32 (s, 3H), 2.52 (s,3H), 2.54 (br t, 1H), 2.68 (m, 1H), 2.82 (m, 2H), 3.28 (m, 1H), 3.50 (m,4H), 3.59 (s, 3H), 3.88 (m, 1H), 4.20 (m, 1H), 6.95 (s+d, 2H), 7.07 (s,1H), 7.34 (m, 1H), 7.81 (s, 1H), 7.98 (br t, 1H), 8.65 (br d, 1H); ES-MSm/z 545 (M+H).

Example 219

Compound 219 4,6-Dimethyl-pyridine-2,5-dicarboxylic acid2-tert-butylamide5-({(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

¹H NMR (CDCl₃) δ 0.81 (m, 1H), 0.98 (d+m, 4H), 1.49 (s+m, 1H), 1.64-1.76(m, 4H), 2.16 (br t, 1H), 2.32 (s, 3H), 2.54 (s+br t, 4H), 2.69 (m, 1H),2.82 (m, 2H), 3.28 (m, 1H), 3.50 (m, 2H), 3.60 (s, 3H), 3.84 (m, 1H),4.18 (m, 1H), 6.94 (s, 1H), 7.01 (d, 1H, J=6.0 Hz), 7.10 (s, 1H), 7.36(m, 1H), 7.84 (s, 1H), 7.99 (s, 1H), 8.64 (br s, 1H); ES-MS m/z 573(M+H).

Example 220

Compound 220 4,6-Dimethyl-pyridine-2,5-dicarboxylic acid 2-cyanomethyl5-({(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

¹H NMR (CDCl₃) δ 0.90 (m, 1H), 0.98 (d+m, 4H), 1.54 (m, 2H), 1.67-1.76(m, 3H), 2.21 (br t, 1H), 2.36 (s, 3H), 2.55 (s+br t, 4H), 2.72 (m, 1H),2.86 (m, 2H), 3.34 (m, 1H), 3.57 (s, 2H), 3.60 (s, 3H), 3.84 (m, 1H),4.20 (m, 1H), 4.38 (d, 2H, J=6.0 Hz), 6.90 (d, 1H, J=3.0 Hz), 7.02 (s,1H), 7.07 (s, 1H), 7.37 (m, 1H), 7.82 (s, 1H), 8.32 (br t, 1H), 8.64 (brs, 1H); ES-MS m/z 556 (M+H).

Example 221

Compound 221 4,6-Dimethyl-pyridine-2,5-dicarboxylic acid 2-sec-butyl5-({(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

¹H NMR (CDCl₃) δ 0.85 (m, 1H), 0.98 (m, 7H), 1.26 (d, 3H, J=6.0 Hz),1.51-1.75 (m, 7H), 2.17 (br t, 1H), 2.33 (s, 3H), 2.55 (s+br t, 4H),2.68 (m, 1H), 2.82 (m, 2H), 3.29 (m, 1H), 3.52 (s, 2H), 3.60 (s, 3H),3.88 (m, 1H), 4.10 (m, 1H), 4.17 (m, 1H), 6.93 (s, 1H), 6.98 (d, 1H,J=3.0 Hz), 7.09 (s, 1H), 7.37 (m, 1H), 7.85 (s+m, 2H), 8.65 (br s, 1H);ES-MS m/z 573 (M+H).

Example 222

Compound 222 4,6-Dimethyl-pyridine-2,5-dicarboxylic acid 2-isobutyl5-({(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

¹H NMR (CDCl₃) δ 0.86 (m, 1H), 0.98 (d+d+m, 11H), 1.56 (m, 1H),1.65-1.74 (m, 4H), 1.91 (m, 1H), 2.18 (br t, 1H), 2.33 (s, 3H), 2.54 (s,3H), 2.57 (br t, 1H), 2.69 (m, 1H), 2.86 (m, 2H), 3.29 (m, 3H), 3.54 (s,2H), 3.60 (s, 3H), 3.86 (m, 1H), 4.23 (m, 1H), 6.96 (s+d, 2H), 7.08 (s,1H), 7.35 (m, 1H), 7.84 (s, 1H), 8.10 (br t, 1H), 8.66 (br s, 1H); ES-MSm/z 573 (M+H).

Example 223

Compound 223 4,6-Dimethyl-pyridine-2,5-dicarboxylic acid 2-allyl5-({(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

¹H NMR (CDCl₃) δ 0.88 (m, 1H), 1.02 (d+m, 4H), 1.56 (m, 1H), 1.65-1.73(m, 4H), 2.17 (br t, 1H), 2.33 (s, 3H), 2.53 (s, 3H), 2.56 (br t, 1H),2.69 (m, 1H), 2.83 (m, 2H), 3.30 (m, 1H), 3.56 (s, 2H), 3.60 (s, 3H),3.84 (m, 1H), 4.10 (t, 2H, J=6.0 Hz), 4.20 (m, 1H), 5.17 (m, 2H), 5.93(m, 1H), 6.93 (s+d, 2H), 7.07 (s, 1H), 7.34 (m, 1H), 7.83 (s, 1H), 8.10(br t, 1H), 8.65 (br s, 1H); ES-MS m/z 557 (M+H).

Example 224

Compound 2242,4-Dimethyl-N—{(R)-3-[4-(3-methyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-6-(pyrrolidine-1-carbonyl)-nicotinamide

¹H NMR (CDCl₃) δ 0.83 (m, 1H), 0.99 (d+m, 4H), 1.56 (m, 1H), 1.65-1.77(m, 4H), 1.94 (m, 4H), 2.17 (br t, 1H), 2.30 (s, 3H), 2.53 (s, 3H), 2.58(br t, 1H), 2.69 (m, 1H), 2.84 (m, 2H), 3.29 (m, 1H), 3.60 (s, 3H),3.62-3.69 (m, 6H), 3.88 (m, 1H), 4.23 (m, 1H), 7.06 (d, 1H, J=6.0 Hz),7.11 (s, 1H), 7.18 (s, 1H), 7.31 (m, 1H), 7.40 (s, 1H), 8.86 (br s, 1H);ES-MS m/z 571 (M+H).

Example 225

Compound 225 4,6-Dimethyl-pyridine-2,5-dicarboxylic acid2-(isopropyl-methyl-amide)5-({(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

¹H NMR (CDCl₃) (mixture of rotamers) δ 0.84 (m, 1H), 0.98 (d+m, 4H),1.15 (d, J=6.0 Hz) and 1.23 (d, J=6.0 Hz) (total 6H), 1.54 (m, 1H),1.65-1.76 (m, 3H), 2.16 (br t, 1H), 2.30 (s, 3H), 2.52 (s, 3H), 2.56 (brt, 1H), 2.68 (m, 1H), 2.83 (m, 2H), 2.78 (s) and 2.95 (s) (total 3H),3.28 (m, 2H), 3.60 (s, 3H), 3.70 (dd, 2H, J=18.0, 12.0 Hz), 3.88 (m) and4.94 (m) (total 1H), 4.24 (m, 1H), 7.06 (d, 1H, J=3.0 Hz), 7.13 (m, 2H),7.19 (s, 1H), 7.29 (m, 1H), 8.89 (br m, 1H); ES-MS m/z 573 (M+H).

Example 226

Compound 226 4,6-Dimethyl-pyridine-2,5-dicarboxylic acid2-(methyl-tert-butyl-amide)5-({(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

¹H NMR (CDCl₃) δ 0.84 (m, 1H), 0.97 (d+m, 4H), 1.54 (s+m, 10H),1.64-1.76 (m, 3H), 2.15 (brt, 1H), 2.30 (s, 3H), 2.52 (s, 3H), 2.56(brt, 1H), 2.67 (m, 1H), 2.79 (m, 2H), 2.83 (s, 3H), 3.27 (m, 2H), 3.58(s, 3H), 3.69 (dd, 2H, J=18.0, 12.0 Hz), 3.80 (m, 1H), 4.23 (m, 1H),7.07 (s+d, 2H), 7.14 (s, 1H), 7.21 (s, 1H), 7.30 (m, 1H), 8.77 (br s,1H); ES-MS m/z 587 (M+H).

Example 227 and Example 228

Compound 227 6-Ethoxy-4-methyl-pyridine-2,5-dicarboxylic acid2-isopropylamide5-({(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

Compound 228 6-Methoxy-4-methyl-pyridine-2,5-dicarboxylic acid2-isopropylamide5-({(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-amide)

To a solution of2-chloro-6-cyano-4-methyl-N-{3-[4-(3-methyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide(0.150 g, 0.30 mmol) in reagent grade (75%) ethanol (5 ml) was added 10N NaOH (1 ml) and the resulting colorless solution was stirred for 6hours at 100° C. The reaction mixture was dry loaded onto silica gel andpurified using column chromatography (MeCN/MeOH/NH₄OH, 6:3:1, v/v/v) togive a mixture of two products,6-methoxy-4-methyl-5-{3-[4-(3-methyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butylcarbamoyl}-pyridine-2-carboxylicacid and6-ethoxy-4-methyl-5-{3-[4-(3-methyl-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butylcarbamoyl}-pyridine-2-carboxylicacid, as a glassy white solid (0.291 g, 80%). ¹H NMR and LC-MS of themixture both confirmed that it was indeed a 1:1 mixture of the methoxyand ethoxy products.

The above acid mixture (0.070 g, 0.13 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydro-chloride (0.028 g,0.14 mmol) and 1-hydroxybenzotriazole (0.020 g, 0.14 mmol) were combinedin N,N-dimethylformamide (5 ml) to give a pale yellow solution. To thissolution was added isopropylamine (12 μL, 0.14 mmol) followed bydiisopropylethylamine (30 μL, 0.16 mmol) and the resulting mixture wasstirred at 25° C. for 16 hours. Standard workup according to generalprocedure E gave the crude product as a tan oil. Purification by columnchromatography on silica gel (Et₂O/MeOH/NH₄OH, 89:10:1, v/v/v) affordedboth COMPOUND 227 (0.035 g, 46%) and COMPOUND 228.

COMPOUND 227: ¹H NMR (CDCl₃) δ 0.98 (d+m, 4H), 1.21 (m, 1H), 1.29 (d,6H, J=6.0 Hz), 1.37 (t, 3H, J=6.0 Hz), 1.53 (m, 1H), 1.72 (m, 3H), 2.18(br t, 1H), 2.33 (s, 3H), 2.56 (br t, 1H), 2.71 (m, 1H), 2.85 (m, 2H),3.30 (m, 1H), 3.60 (s, 3H), 3.64 (s, 2H), 3.79 (m, 1H), 4.24 (m, 2H),4.35 (q, 2H, J=6.0 Hz), 6.92 (s+d, 2H), 7.07 (s, 1H), 7.34 (m, 1H), 7.49(d, 1H, J=6.0 Hz), 7.63 (s, 1H), 8.26 (br d, 1H); ES-MS m/z 589 (M+H).

COMPOUND 228: ¹H NMR (CDCl₃) δ 0.98 (d+m, 4H), 1.19 (m, 1H), 1.29 (d,6H, J=6.0 Hz), 1.53 (m, 1H), 1.74 (m, 3H), 2.17 (br t, 1H), 2.34 (s,3H), 2.58 (br t, 1H), 2.71 (m, 1H), 2.85 (m, 2H), 3.30 (m, 1H), 3.60 (s,3H), 3.64 (s, 2H), 3.79 (m, 1H), 3.93 (s, 3H), 4.28 (m, 2H), 6.92 (s+d,2H), 7.06 (s, 1H), 7.34 (m, 1H), 7.51 (d, 1H, J=6.0 Hz), 7.65 (s, 1H),8.32 (br d, 1H); ES-MS m/z 575 (M+H).

Example 229

Compound 2292,4-Dimethyl-N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-6-(2H-tetrazol-5-yl)-nicotinamide

6-Cyano-2,4-dimethyl-N-{3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide(0.21 g, 0.42 mmol) was dissolved in iso-propanol (4 ml) and dilutedwith water (8 ml) (Demke and Sharpless, JOC 2001, 66, 7945-50). To themilky solution were added ZnBr₂ (0.094 g, 0.42 mmol) and NaN₃ (0.030 g,0.46 mmol) and the resulting mixture was refluxed for 16 h. The crudereaction mixture was dry-loaded onto silica gel and purified via columnchromatography (MeCN/MeOH/NH₄OH, 7:2:1, v/v/v) to yield COMPOUND 229(0.13 g, 58%) as a white solid. ¹H NMR (CD₃OD) δ 1.49 (d, 3H, J=6.0 Hz),1.98 (m, 3H), 2.29 (m, 3H), 2.40 (s, 3H), 2.60 (s, 3H), 3.28 (m, 2H),3.58 (m, 5H), 4.23 (m, 1H), 4.48 (s, 2H), 7.08 (d, 1H, J=6.0 Hz), 7.26(s, 1H), 7.44 (m, 1H), 7.87 (s, 1H); ES-MS m/z 542 (M+H).

Example 230

Compound 2302,4-Dimethyl-6-(2-methyl-2H-tetrazol-5-yl)-N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-nicotinamide

In a high-pressure sealed tube, methyl iodide (24 μL, 0.39 mmol) andK₂CO₃ (0.10 g, 0.78 mmol) were added to a solution of2,4-dimethyl-N-{3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-butyl}-6-(2H-tetrazol-5-yl)-nicotinamide(0.070 g, 0.13 mmol) dissolved in DMF (4 ml). The resulting mixture wasstirred at 80° C. for 16 h. Standard basic workup gave the crude productas a tan oil. Purification by column chromatography on silica gel(Et₂O/MeOH/NH₄OH, 87:11:2, v/v/v) afforded COMPOUND 230 (0.015 g, 21%)as a white foam. ¹H NMR (CDCl₃) δ 0.91-1.11 (d+m, 5H), 1.54 (m, 1H),1.69-1.81 (m, 3H), 2.21 (brt, 1H), 2.40 (s, 3H), 2.59 (s+br t, 4H), 2.63(m, 1H), 2.75 (m, 2H), 3.35 (m, 1H), 3.50 (s, 2H), 3.55 (s, 3H), 3.88(m, 1H), 4.21 (m, 1H), 4.34 (s, 3H), 6.73 (d, 1H J=3.0 Hz), 6.86 (s,2H), 7.28 (m, 1H), 8.00 (s, 1H), 8.85 (br s, 1H). ES-MS m/z 556 (M+H).

Example 231

Compound 231N—{(R)-3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin1-yl]-butyl}-6-(N-hydroxycarbamimidoyl)-2,4-dimethyl-nicotinamide

To a solution of6-cyano-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(208 mg, 0.49 mmol) in EtOH (3 ml) was added hydroxylamine HCl (190 mg,2.73 mmol) and NaHCO₃ (239 mg, 2.84 mmol) and the reaction heated toreflux overnight. The mixture was diluted with CH₂Cl₂ (25 ml) and water(10 ml) and saturated aqueous NaHCO₃ (20 ml). The aqueous layer wasextracted with CH₂Cl₂ (2×5 ml) and the combined organic extracts weredried (Na₂SO₄) and concentrated to afford6-(N-hydroxycarbamimidoyl)-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(173 mg) as a beige foam.

To a solution of the amine from above (173 mg) in CH₂Cl₂ (5 ml) wasadded DIPEA (0.080 ml, 0.46 mmol) andN-(4-nitrophenoxycarbonyl)methoxylamine (89 mg, 0.42 mmol) and thereaction stirred at room temperature for 2 h. The mixture was dilutedwith CH₂Cl₂ (25 ml) and saturated aqueous NaHCO₃ (25 ml) and the aqueouslayer was extracted with CH₂Cl₂ (2×10 ml), dried (Na₂SO₄), concentratedand purified by column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH,96:4:0 then 9:1:0 then 88:10:2) to afford COMPOUND 231 (123 mg, 47% 2steps) as a yellow foam. ¹H NMR (CDCl₃) δ 1.03 (d, 3H, J=6.6 Hz),1.06-1.47 (m, 2H), 1.67-1.90 (m, 4H), 2.21-2.28 (m, 1H), 2.24 (s, 3H),2.45 (s, 3H), 2.61 (br t, 1H, J=11.4 Hz), 2.75-2.94 (m, 3H), 3.47-3.53(m, 1H), 3.61-3.65 (m, 1H), 3.63 (s, 3H), 3.90 (s, 2H), 4.21-4.28 (m,1H), 5.54 (br s, 2H), 6.93 (dd, 1H, J=4.8, 1.2 Hz), 7.07 (br s, 1H),7.09 (s, 1H), 7.19 (s, 1H), 7.31 (dd, 1H, J=4.8, 3 Hz), 8.22 (br m, 1H),9.39 (br s, 1H); ES-MS m/z 554 (M+Na).

Example 232

Compound 2322,6-Dichloro-N—{(R)-3-[4-(1-cyclohexylmethyl-3-methoxy-ureido)-piperidin-1-yl]-butyl}-4-methyl-nicotinamide

To a solution of{(R)-3-[4-(cyclohexylmethyl-amino)-piperidin-1-yl]-butyl}-carbamic acidtert-butyl ester (174 mg, 0.47 mmol) in THF (5 ml) was addedmethoxy-carbamic acid phenyl ester (94.7 mg, 0.56 mmol). The mixture wasstirred at 60° C. for 3 d then concentrated in vacuo. The crude productwas purified by flash chromatography (CH₂Cl₂, 7% MeOH, 1% NH₄OH) toafford{(R)-3-[4-(1-cyclohexylmethyl-3-methoxy-ureido)-piperidin-1-yl]-butyl}-carbamicacid tert-butyl ester (105 mg, 50%) as a yellow oil.

Following general procedure C: To a solution of the boc-protected amine(105 mg, 0.23 mmol) in CH₂Cl₂ (5 ml) was added TFA (1 ml). The reactionwas stirred at room temperature for 2 h then concentrated to removeexcess TFA. The crude product was used in the next reaction withoutpurification. Following general procedure E:1-[1-((R)-3-Amino-1-methyl-propyl)-piperidin-4-yl]-1-cyclohexylmethyl-3-ethyl-urea(77 mg, 0.23 mmol), 2,6-dichloro-4-methyl-nicotinic acid (51 mg, 0.25mmol), EDCI (48 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol), DIPEA (0.059ml, 0.35 mmol), and DMF (5 ml) were combined and stirred at roomtemperature overnight. The crude product was purified by preparative TLC(ether, 8% MeOH, 1% NH₄OH) to afford COMPOUND 232 (63 mg, 51%, 2 steps)as a white solid. ¹H NMR (CDCl₃) δ 0.75-0.91 (m, 2H), 0.99 (d, 3H, J=6.0Hz), 1.11-1.28 (m, 4H), 1.32-1.50 (m, 2H), 1.51-1.83 (m, 9H), 2.07-2.17(m, 1H), 2.38 (s, 3H), 2.48-2.64 (m, 3H), 2.74-2.87 (m, 3H), 3.27-3.44(m, 1H), 3.70 (s, 3H), 3.71-3.93 (m, 2H), 7.07 (s, 1H), 7.15 (s, 1H),8.21 (br s, 1H); ES-MS m/z 528 (M+H).

Example 233

Compound 2332,6-Dichloro-4-methyl-N-{3-[4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidin-1-yl]-propyl}-nicotinamide

Using general procedure A, 4-amino-piperidine-1-carboxylic acidtert-butyl ester (0.800 g, 4.30 mmol), thiophene-3-carbaldehyde (0.480g, 4.30 mmol), acetic acid (20 drops, cat.) and sodiumtriacetoxyborohydride (1.27 g, 6.02 mmol) were combined in1,2-dichloroethane (40 ml) and the resulting mixture was stirred at rtfor 16 h. Standard basic workup gave the crude product as a tan oil.Purification by column chromatography on silica gel (CH₂Cl₂:MeOH:NH₄OH,96:3:1, v/v/v) gave4-[(thiophen-3-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butylester as a pale yellow oil (0.886 g, 73%). ¹H-NMR (CDCl₃) δ 1.27 (m,3H), 1.45 (s+m, 1H), 1.84 (d, 2H, J=12.0 Hz), 2.66 (m, 1H), 2.80 (t, 2H,J=12.0 Hz), 3.85 (s, 2H), 4.01 (br d, 2H), 7.03 (d, 1H, J=6.0 Hz), 7.12(s, 1H), 7.29 (m, 1H).

To a suspension of methoxylamine hydrochloride (0.520 g, 6.25 mmol) inCH₃CN (15 ml) was added DIPEA (1.09 ml, 6.25 mmol) followed by CDI (1.02g, 6.25 mmol) and the reaction stirred at rt for 1.5 h after which asolution of the amine from above (0.880 g, 3.12 mmol) in CH₃CN (10 ml)was added and the reaction stirred at 60° C. overnight. The solution wascooled, treated with saturated aqueous NaHCO₃ (20 ml) and extracted withCH₂Cl₂ (3×15 ml). The combined organic extracts were dried (Na₂SO₄),filtered, and concentrated. Purification by column chromatography onsilica gel (CH₂Cl₂:MeOH:NH₄OH, 96:3:1, v/v/v) gave4-(3-methoxy-1-thiophen-3-ylmethyl-ureido)-piperidine-1-carboxylic acidtert-butyl ester as a white foam (0.95 g, 86%). ¹H-NMR (CDCl₃) δ 1.43(s, 9H), 1.54 (m, 1H), 1.75 (d, 2H, J=9.0 Hz), 2.79 (br t, 1H), 3.65 (s,3H), 4.17 (m, 2H), 4.27 (s, 2H), 6.96 (d, 1H, J=3.0 Hz), 7.08 (s, 1H),7.11 (s, 1H), 7.36 (m, 1H).

4-(3-Methoxy-1-thiophen-3-ylmethyl-ureido)-piperidine-1-carboxylic acidtert-butyl ester (0.950 g, 2.69 mmol) was dissolved in a 3:1 mixture ofCH₂Cl₂ and TFA and the mixture was stirred at rt for 1 h. The solventwas removed in vacuo and the resulting brown oil pumped in vacuo (highvacuum system) for 2 h. Using general procedure A, the crude amine,3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde (0.561 g, 2.75mmol), acetic acid (20 drops, cat.) and sodium triacetoxyborohydride(0.792 g, 3.75 mmol) were combined in CH₂Cl₂ (40 ml) and the resultingmixture was stirred at rt for 16 h. Standard basic workup gave the crudeproduct as a tan oil. Purification by column chromatography on silicagel (CH₂Cl₂:MeOH:NH₄OH, 94:5:1, v/v/v) gave1-{1-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-piperidin-4-yl}-3-methoxy-1-thiophen-3-ylmethyl-ureaas a white foam (0.692 g, 62%). ¹H NMR (CDCl₃) δ 1.36 (m, 2H), 1.59 (m,2H), 1.85 (p, 2H, J=4.5 Hz), 1.91 (t, 2H, J=9.0 Hz), 2.39 (t, 2H, J=6.0Hz), 2.88 (d, 2H, J=12.0 Hz), 3.62 (s, 3H), 3.75 (t, 2H, J=6.0 Hz), 4.04(s, 2H), 4.23 (m, 1H), 6.90 (d, 1H, J=3.0 Hz), 6.99 (s, 1H), 7.06 (s,1H), 7.36 (m, 1H), 7.62 (m, 2H), 7.81 (m, 2H).

To a solution of1-{1-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-piperidin-4-yl}-3-methoxy-1-thiophen-3-ylmethyl-urea(0.69 g, 1.56 mmol) in EtOH (15 ml) was added hydrazine hydrate (0.49ml, 15.6 mmol) and the reaction was stirred at rt for 16 h. The reactionmixture was diluted with Et₂O (40 ml) to give a white precipitate. Thesolid was removed via suction filtration and the filtrate wasconcentrated in vacuo to give a white foam. Purification by columnchromatography on silica gel (CH₂Cl₂:MeOH:NH₄OH, 83:15:2, v/v/v) gave1-[1-(3-amino-propyl)-piperidin-4-yl]-3-methoxy-1-thiophen-3-ylmethyl-ureaas a white foam (0.280 g, 57%). ¹H NMR (CDCl₃) δ 1.60-1.72 (m, 6H), 2.00(t, 2H, J=9.0 Hz), 2.07 (br s, 3H), 2.39 (t, 2H, J=6.0 Hz), 2.75 (t, 2H,J=6.0 Hz), 2.98 (d, 2H, J=12.0 Hz), 3.65 (s, 3H), 4.25 (m, 1H), 4.29 (s,2H), 6.95 (d, 1H, J=3.0 Hz), 7.10 (s, 2H), 7.34 (m, 1H).

The above amine (0.059 g, 0.19 mmol), EDCI (0.040 g, 0.21 mmol) and HOBt(0.028 g, 0.21 mmol) were combined in DMF (8 ml) to give a pale yellowsolution. To this solution was added 2,6-dichloro-4-methyl-nicotinicacid (0.043 g, 0.21 mmol) followed by DIPEA (43 μL, 0.24 mmol) and theresulting mixture was stirred at 25° C. for 16 h. Standard workupaccording to general procedure E gave the crude product as a tan oil.Purification by column chromatography on silica gel (Et₂O:MeOH:NH₄OH,86:12:2, v/v/v) afforded COMPOUND 233 (0.067 g, 69%) as a white foam. ¹HNMR (CDCl₃) δ 1.26 (m, 2H), 1.70-1.79 (m, 4H), 2.06 (t, 2H, J=12.0 Hz),2.35 (s, 3H), 2.54 (t, 2H, J=6.0 Hz), 2.97 (m, 2H), 3.57 (m, 2H), 3.63(s, 3H), 3.95 (s, 2H), 4.27 (m, 1H), 6.98 (d, 1H, J=6.0 Hz), 7.06 (s,1H), 7.10 (m, 2H), 7.36 (m, 1H), 8.36 (br t, 1H); ES-MS m/z 536 (M+Na).Anal. Calcd. for C₂₂H₂₉N₅O₃Cl₂S·1.1H₂O: C, 49.46; H, 5.89; N, 13.11.Found: C, 49.42; H, 5.63; N, 12.84.

Example 234

Compound 2342,6-Dichloro-N—((R)-3-{4-[1-(3-chloro-benzyl)-3-methoxy-ureido]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

Following general procedure A: to a solution of[(R)-3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester(0.25 g, 0.94 mmol) in CH₂Cl₂ (20 ml) was added 3-chloro-benzylamine(0.14 ml, 1.13 mmol) and the mixture was stirred for 5 min. NaBH(OAc)₃(0.30 g, 1.41 mmol) and acetic acid (10 drops) were added and themixture was stirred at rt under N₂ overnight. The crude product waspurified by flash chromatography (CH₂Cl₂, 5% MeOH, 1% NH₄OH) to afford{(R)-3-[4-(3-chloro-benzylamino)-piperidin-1-yl]-butyl}-carbamic acidtert-butyl ester as a yellow oil (305 mg, 82%). ¹H NMR (CDCl₃) δ0.92-0.94 (d, 3H, J=6 Hz), 1.27-1.39 (m, 2H), 1.44 (s, 9H), 1.60-1.72(m, 2H), 1.82-1.97 (m, 2H), 2.02-2.14 (m, 1H), 2.32-2.51 (m, 2H),2.68-2.87 (m, 3H), 3.05-3.11 (m, 1H), 3.23-3.37 (m, 1H), 3.79 (s, 2H),4.40 (s, 1H), 6.01 (br s, 1H), 7.16-7.25 (m, 3H), 7.33 (s, 1H).

To a solution of methoxyamine HCl (0.25 g, 3.04 mmol) in CH₃CN (5 ml)was added CDI (0.49 g, 3.04 mmol) and DIPEA (0.53 mL, 3.04 mmol). Themixture was stirred at 60° C. for 2 h, then a solution of{(R)-3-[4-(3-chloro-benzylamino)-piperidin-1-yl]-butyl}-carbamic acidtert-butyl ester (305 mg, 0.76 mmol) in CH₃CN (5 ml) was added to theprevious mixture. After stirring at 60° C. overnight, the mixture wasconcentrated in vacuo and diluted with CH₂Cl₂ (15 ml) and saturatedNaHCO₃ (20 ml). The aqueous layer was extracted with CH₂Cl₂ (3×10 ml),then the combined organic extracts were dried over Na₂SO₄ andconcentrated. The crude product contained 2:1 product/starting materialin the ¹H NMR and was purified by flash chromatography (CH₂Cl₂, 7% MeOH,1% NH₄OH) to afford((R)-3-{4-[1-(3-chloro-benzyl)-3-methoxy-ureido]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester as a yellow oil (215 mg, 60%). ¹H NMR (CDCl₃) δ0.92-0.95 (d, 3H, J=9 Hz), 1.37 (s, 9H), 1.47-1.82 (m, 6H), 2.13-2.25(m, 1H), 2.48-2.57 (m, 1H), 2.63-2.89 (m, 3H), 2.99-3.09 (m, 1H),3.23-3.38 (m, 1H), 3.65 (s, 3H), 4.14-4.26 (m, 1H), 4.31 (s, 2H), 5.90(br s, 1H), 6.97 (s, 1H), 7.06-7.17 (m, 1H), 7.22 (s, 1H), 7.29 (s, 1H),7.69 (s, 1H).

Following general procedure C: to a solution of the above Boc-protectedamine (215 mg, 0.46 mmol) in CH₂Cl₂ (5 ml) was added TFA (1 ml). Thereaction was stirred at rt for 1 h then concentrated. The crude1-[1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-1-(3-chloro-benzyl)-3-methoxy-ureawas used in the next reaction without purification.

Following general procedure E:1-[1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-1-(3-chloro-benzyl)-3-ethyl-urea(77 mg, 0.21 mmol), 2,6-dichloro-4-methyl-nicotinic acid (48 mg, 0.23mmol), EDCI (44 mg, 0.23 mmol), HOBt (31 mg, 0.23 mmol), DIPEA (0.055ml, 0.32 mmol), and DMF (5 ml) were combined and stirred at rtovernight. The crude product was purified by preparative TLC (ether, 6%MeOH, 2% NH₄OH) to afford COMPOUND 234 as a white solid (81 mg, 62%, 2steps). ¹H NMR (CDCl₃) δ 0.99-1.01 (d, 3H, J=6 Hz), 1.12-1.26 (m, 1H),1.49-1.57 (m, 1H), 1.62-1.86 (m, 4H), 2.13-2.26 (m, 1H), 2.34 (s, 3H),2.51-2.64 (m, 1H), 2.72-2.93 (m, 3H), 3.25-3.44 (m, 1H), 3.63 (s, 3H),3.72-3.82 (m, 1H), 3.89 (s, 2H), 4.06-4.24 (m, 1H), 6.90 (s, 1H), 7.10(s, 1H), 7.14-7.16 (d, 1H, J=6 Hz), 7.21 (s, 1H), 7.28 (s, 1H),7.31-7.34 (d, 1H, J=9 Hz), 8.59 (br s, 1H); ¹³C NMR (CDCl₃): δ 13.50,19.21, 29.79, 30.50, 30.74, 39.78, 43.64, 44.53, 51.50, 53.02, 59.89,64.30, 124.31, 124.46, 126.15, 127.93, 130.42, 132.52, 135.06, 139.86,146.61, 149.90, 151.05, 159.18, 164.27; ES-MS m/z 556 (M+H).

Example 235

Compound 2356-Chloro-N—{(R)-3-[4-(methanesulfonyl-thiophen-3-ylmethyl-amino)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

To a solution of((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (154 mg, 0.42 mmol) in CH₂Cl₂ (5 ml) at 0° C. wasadded DIPEA (0.20 ml, 1.15 mmol) and MsCl (0.08 ml, 1.03 mmol) and thereaction stirred from 0° C. to rt over 1.5 h. The mixture was dilutedwith saturated aqueous NaHCO₃ (20 ml) and extracted with CH₂Cl₂ (3×10ml). The combined organic extracts were dried (Na₂SO₄), filtered, andconcentrated. To a solution of the crude mesylate from above in CH₂Cl₂(1.5 ml) was added TFA (1.5 ml) and the reaction stirred for 1 h thenconcentrated in vacuo.

Following general procedure E: to a solution of the resultant crudeproduct from above in DMF (2 ml) was added6-chloro-2,4-dimethyl-nicotinic acid (94 mg, 0.42 mmol), HOBt (75 mg,0.56 mmol), DIPEA (0.4 ml, 2.30 mmol) and EDCI (104 mg, 0.54 mmol) andthe reaction stirred overnight. Purification of the crude product byradial chromatography on silica gel (1 mm plate, CH₂Cl₂/MeOH, 96:4 then92:8) afforded COMPOUND 235 (18 mg, 8% over 3 steps) as a white foam. ¹HNMR (CDCl₃) δ 0.97 (d, 3H, J=6.6 Hz), 1.15-1.43 (m, 2H), 1.56-1.75 (m,3H), 2.07-2.14 (m, 1H), 2.31 (s, 3H), 2.45-2.52 (m, 1H), 2.52 (s, 3H),2.64 (s, 3H), 2.70-2.84 (m, 4H), 3.26-3.36 (m, 1H), 3.56-3.64 (m, 1H),3.73-3.84 (m, 1H), 3.93 (d, 1H, J=15 Hz), 4.03 (d, 1H, J=15 Hz), 6.97(s, 1H), 7.03 (d, 1H, J=4.8 Hz), 7.16-7.18 (m, 1H), 7.29 (dd, 1H, J=4.8,3 Hz), 8.06 (br d, 1H); ¹³C NMR (CDCl₃) δ 15.14, 20.55, 23.86, 32.78,32.96, 33.79, 41.48, 43.09, 43.86, 45.46, 53.63, 58.14, 61.70, 124.40,125.10, 127.93, 129.19, 134.33, 140.47, 149.17, 152.10, 156.97, 168.98;ES-MS m/z 535 (M+Na). Anal. Calcd. for C₂₃H₃₃N₄O₃S₂Cl·1.3CH₃OH: C,52.61; H, 6.94; N, 10.10. Found: C, 52.70; H, 6.57; N, 9.87.

Example 236

Compound 236(1-(R)—{3-[(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-carbamicacid ethyl ester

To a solution of((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (251 mg, 0.68 mmol) in CH₂Cl₂ (5 ml) was addedethyl chloroformate (143 μL, 1.50 mmol). The reaction was stirred for 3h before being diluted with CH₂Cl₂ (40 ml) and washed with 1N NaOH (15ml). The solution was dried over Na₂SO₄, concentrated, and purified byflash chromatography (MeOH/CH₂Cl₂, 5%) to give the desired product (269mg, 90%).

Following general procedure C: the Boc-protected amine was taken up inCH₂Cl₂ (8 ml) and TFA (2 mL) was added. The reaction was allowed to stirfor 2 h before solvent was removed. The crude was diluted with CH₂Cl₂and washed with 1N NaOH before the organic layer was isolated and driedover Na₂SO₄. The crude residue was used as is in the next step.

Following general procedure E: to a solution of the resultant crudeproduct from above in DMF (4 ml) was added6-chloro-2,4-dimethylnicotinic acid (75 mg, 0.34 mmol), HOBt (57 mg,0.42 mmol), DIPEA (1 ml, 5.7 mmol) and EDCI (82 mg, 0.43 mmol) and thereaction stirred overnight. Purification of the crude product by flashchromatography on silica gel (MeOH/CH₂Cl₂, 3%) afforded COMPOUND 236 (17mg, 10% over 3 steps) as a white foam. ¹H NMR (CDCl₃) δ 0.94 (d, 3H, J=6Hz), 1.22 (m, 4H), 1.59 (m, 4H), 1.61-1.78 (m, 2H), 2.04 (m, 1H), 2.32(s, 3H), 2.53 (s, 3H), 2.62-2.81 (m, 3H), 3.28 (t, 1H, J=12 Hz),3.74-3.98 (m, 3H), 4.12 (m, 3H), 6.99 (m, 1H), 7.02 (s, 1H), 7.23 (m,1H); ES-MS m/z 529 (M+Na).

Example 237

Compound 2376-Chloro-N—{(R)-3-[4-(3-ethyl-1-thiophen-3-ylmethyl-thioureido)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

To a solution of6-chloro-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(76 mg, 0.18 mmol) in CH₂Cl₂ (5 ml) was added ethyl isothiocyanate (30μL, 0.34 mmol) and the reaction stirred at rt overnight. The mixture wasconcentrated and purified by column chromatography on silica gel(CH₂Cl₂/MeOH, 96:4) to provide COMPOUND 237 (34 mg, 36%) as a whitefoam. ¹H NMR (CDCl₃) δ 0.85-0.95 (m, 1H), 098-1.03 (m, 7H), 1.48-1.82(m, 5H), 2.23-2.31 (m, 1H), 2.28 (s, 3H), 2.48 (s, 3H), 2.63-2.87 (m,4H), 3.21-3.28 (m, 1H), 3.53-3.59 (m, 2H), 3.84-3.91 (m, 3H), 5.38 (brs, 1H), 6.96 (s, 1H), 7.05 (d, 1H, J=4.8 Hz), 7.12-7.14 (m, 1H), 7.38(dd, 1H, J=4.8, 3 Hz), 8.93 (br s, 1H); ¹³C NMR (CDCl₃) δ 13.86, 14.64,19.14, 22.44, 29.57, 30.07, 30.80, 40.63, 41.23, 43.51, 44.06, 52.20,57.74, 61.22, 122.01, 122.86, 126.22, 128.02, 133.32, 137.56, 148.09,150.38, 155.79, 167.34, 182.46; ES-MS m/z 544 (M+Na). Anal. Calcd. forC₂₅H₃₆N₅OS₂Cl·0.2H₂O·0.2CH₂Cl₂: C, 55.77; H, 6.83; N, 12.90. Found: C,55.94; H, 6.80; N, 12.55.

Example 238

Compound 238(1-{(R)-3-[(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-thiocarbamicacid S-methyl ester

To a solution of((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (139 mg, 0.38 mmol) in CH₂Cl₂ (8 mL) was addedthiomethylchloroformate (39 μL, 0.46 mmol) and DIPEA (160 μL, 0.91mmol). The reaction was stirred overnight and then diluted with CH₂Cl₂(25 ml) and washed with 1N NaOH (10 ml) and dried over Na₂SO₄. The cruderesidue was sufficiently pure to be used in the next step withoutfurther purification.

Following general procedure C: the Boc-protected amine was taken up inCH₂Cl₂ (8 ml) and TFA (2 ml) was added. The reaction was allowed to stirfor 2 h before solvent was removed. The crude was diluted with CH₂Cl₂and washed with 1N NaOH before the organic layer was isolated and driedover Na₂SO₄. The crude residue was purified by flash chromatography(MeOH/CH₂Cl₂/NH₄OH, 5:95:1) to give the desired amine (118 mg, 91% over2 steps).

Following general procedure E: to a solution of the primary amine fromabove in DMF (4 ml) was added 6-chloro-2,4-dimethylnicotinic acid (85mg, 0.38 mmol), HOBt (71 mg, 0.53 mmol), DIPEA (1 ml, 5.7 mmol) and EDCI(100 mg, 0.52 mmol) and the reaction stirred overnight. Purification ofthe crude product by flash chromatography on silica gel (MeOH/CH₂Cl₂,2%) afforded COMPOUND 238 (107 mg, 61%) as a white foam. ¹H NMR (CDCl₃)δ 0.96 (d, 3H, J=9 Hz), 1.01-1.26 (m, 4H), 1.49-1.83 (m, 5H), 2.09 (t,1H, J=12 Hz), 2.31 (s, 3H), 2.32 (s, 3H), 2.46 (t, 1H, J=12 Hz), 2.51(s, 3H), 2.68-2.81 (m, 3H), 3.24-3.29 (m, 1H), 3.75-3.84 (m, 1H),3.96-4.21 (m, 1H), 6.99-7.08 (m, 3H), 7.26 (s, 1H); ES-MS m/z 510 (M+H).

Example 239

Compound 2396-Chloro-2,4-dimethyl-N—{(R)-3-[4-(3-methyl-1-thiophen-3-ylmethyl-thioureido)-piperidin-1-yl]-butyl}-nicotinamide

Following general procedure H,6-chloro-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamideand isothiocyanate afforded COMPOUND 239. ¹H NMR (CDCl₃) δ 0.72-0.83 (m,1H), 0.97-1.01 (m, 1H), 0.98 (d, 3H, J=6.6 Hz), 1.48-1.63 (m, 1H),1.71-1.82 (m, 3H), 2.18-2.24 (m, 1H), 2.28 (s, 3H), 2.48 (s, 3H),2.58-2.68 (m, 2H), 2.79-2.84 (m, 2H), 3.03 (d, 3H, J=3 Hz), 3.20-3.28(m, 1H), 3.85-3.94 (m, 3H), 5.27-5.35 (m, 1H), 5.49 (br s, 1H), 6.99 (s,1H), 7.09 (dd, 1H, J=5.1, 0.9 Hz), 7.10-7.11 (m, 1H), 7.39 (dd, 1H,J=5.1, 3 Hz), 8.98 (br d, 1H); ¹³C NMR (CDCl₃) δ 13.77, 19.17, 22.46,29.17, 30.08, 30.93, 33.35, 40.35, 43.67, 44.24, 52.17, 57.78, 61.11,121.88, 122.90, 126.22, 127.99, 129.25, 137.49, 148.09, 150.42, 155.78,167.46, 183.82; ES-MS m/z 508 (M+H). Anal. Calcd. forC₂₄H₃₄N₅OS₂Cl·0.2CH₂Cl₂·0.1H₂O: C, 55.16; H, 6.62; N, 13.29. Found: C,55.15; H, 6.72; N, 13.03.

Example 240

Compound 2404-Cyano-2,6-dimethyl-N—{(R)-3-[4-(3-methyl-1-thiophen-3-ylmethyl-thioureido)-piperidin-1-yl]-butyl}-benzamide

Following general procedure H: to((R)-3-{4-[(Thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (1.0 g, 2.72 mmol) in dry CH₂Cl₂ (20 ml) was addedmethylisothiocyanate (223 μl, 3.26 mmol). The reaction mixture was thenallowed to stir at room temperature overnight under N₂ pressure to yield{(R)-3-[4-(3-methyl-1-thiophen-3-ylmethyl-thioureido)-piperidin-1-yl]-butyl}-carbamicacid tert-butyl ester as yellow oil.

The BOC-protected amine was dissolved in CH₂Cl₂ (˜4 ml/mmol) and TFA (2ml/mmol) was added. The mixture was stirred at room temperature for 20min. In a standard work-up, the mixture was neutralized with saturatedaqueous NaHCO₃ and the aqueous extracted with CH₂Cl₂. The combinedextracts were dried with Na₂SO₄, filtered and concentrated under reducedpressure to afford the desired amine.

Following general procedure E: to a stirred solution of1-[1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-3-methyl-1-thiophen-3-ylmethyl-thiourea(145 mg, 0.426 mmol), 4-cyano-2,6-dimethyl-benzoic acid (82 mg, 0.469mmol), HOBt (75 mg, 0.554 mmol) and DIPEA (186 μl, 1.06 mmol) in CH₂Cl₂(3 ml) was added EDCI (106 mg, 0.554 mmol). The solution was stirred atroom temperature for overnight and concentrated in vacuo. In a standardwork-up, the mixture was diluted with CH₂Cl₂ and washed consecutivelywith saturated aqueous NaHCO₃ and brine. The organic layer was driedwith Na₂SO₄, filtered and concentrated under reduced pressure. The crudematerial was purified by tron (DCM, 2% MeOH, 2% NH₄OH) to yield COMPOUND240 as a white foam (70 mg, 33% over 3 steps). ¹H NMR (CDCl₃) δ0.79-0.85 (m, 1H), 0.97-1.01 (m, 4H), 1.49-1.55 (m, 1H), 1.72-1.86 (m,3H), 2.19-2.28 (m; 1H), 2.31 (s, 6H), 2.60-2.74 (m, 2H), 2.83-2.86 (m,2H), 2.98-2.99 (d, 3H, J=4.2 Hz), 3.24-3.30 (m, 1H), 3.77 (s, 2H),3.86-3.93 (m, 1H), 5.33-5.47 (m, 2H), 6.93-6.95 (m, 1H), 7.12-7.13 (d,1H, J=3 Hz), 7.21 (s, 2H), 7.41-7.44 (m, 1H), 8.82-8.84 (br d, 1H);ES-MS m/z 498 (M+H).

Example 241

Compound 241(1-{(R)-3-[(2,6-Dichloro-4-methyl-pyridine-3-carbonyl)-amino]-1methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-thiocarbamic acidS-methyl ester

Following general procedure E the amine (see EXAMPLE 238) and2,6-dichloro-4-methylnicotinic acid afforded COMPOUND 241. ¹H NMR(CDCl₃) δ 0.99 (d, 3H, J=6 Hz), 1.08-1.42 (m, 4H), 1.43-1.81 (m, 4H),2.07-2.14 (m, 1H), 2.32 (s, 2H), 2.37 (s, 3H), 2.43-2.51 (m, 1H),2.73-2.81 (m, 3H), 3.25-3.41 (m, 1H), 3.76-3.84 (m, 1H), 4.04-4.27 (m,2H), 7.01 (d, 1H, J=6 Hz), 7.08 (s, 1H), 7.15 (s, 1H), 7.22 (s, 1H),8.47 (br s, 1H); ES-MS m/z 529 (M+H).

Example 242

Compound 2422,6-Dichloro-4-methyl-N—{(R)-3-[4-(3-methyl-1-thiophen-3-ylmethyl-sulfonamido)-piperidin-1-yl]-butyl}-nicotinamide

To a suspension of methylsulfamic acid (55 mg, 0.49 mmol) in benzene (2ml) was added PCl₅ (98 mg, 0.47 mmol) and the reaction stirred at refluxfor 1.5 h. The mixture was then concentrated and diluted with1,2-dichloroethane (3 ml).2,6-Dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(63 mg, 0.14 mmol) and DIPEA (0.20 ml, 1.15 mmol) were added and thereaction stirred at room temperature overnight. The mixture was dilutedwith CH₂Cl₂ (20 ml) and 1 N NaOH (20 ml) and the aqueous layer wasextracted with CH₂Cl₂ (20 ml). The combined organic extracts were dried(Na₂SO₄) and the resultant crude purified by column chromatography onsilica gel (CH₂Cl₂/MeOH, 96:4 then 9:1) to afford COMPOUND 242 (25 mg,33%) as a white foam. ¹H NMR (CDCl₃) δ 0.98 (d, 3H, J=6.6 Hz), 1.24-1.46(m, 3H), 1.72-1.80 (m, 3H), 2.04-2.14 (m, 1H), 2.36 (s, 3H), 2.43-2.53(m, 1H), 2.43 (d, 3H, J=5.4 Hz), 2.77-2.90 (m, 3H), 3.28-3.36 (m, 1H),3.42-3.51 (m, 1H), 3.77-3.86 (m, 2H), 3.98 (s, 2H), 7.02 (d, 1H, J=4.8Hz), 7.08 (s, 1H), 7.17 (br s, 1H), 7.28 (dd, 1H, J=4.8, 3 Hz), 8.42 (brd, 1H); ¹³C NMR (CDCl₃) δ 13.71, 19.57, 29.51, 30.90, 31.14, 31.66,40.29, 43.49, 44.15, 52.38, 57.46, 60.41, 123.56, 124.96, 126.54,127.90, 132.73, 139.42, 146.85, 150.54, 151.18, 164.75; ES-MS m/z 548(M+H). Anal. Calcd. for C₂₂H₃₁N₅O₃S₂Cl₂·0.3C₆H₆·0.9H₂O: C, 48.60; H,5.93; N, 11.91. Found: C, 48.61; H, 6.00; N, 11.96.

Example 243

Compound 243 2,6-Dichloro-4-methyl-N—{(R)-3-[4-(3-formyl ethylester-1-thiophen-3-ylmethyl-thioureido)-piperidin-1-yl]-butyl}-nicotinamide

To a solution of2,6-dichloro-4-methyl-N-(3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(0.095 g, 0.21 mmol) in methylene chloride (4 ml) was addedisothiocyanatoformate (38 μL, 0.33 mmol) and the resulting mixture wasstirred at 25° C. for 16 hours. Standard basic workup gave the crudeproduct as a tan oil. Purification by column chromatography on silicagel (CH₂Cl₂₁MeOH/NH₄OH, 97:2:1) afforded COMPOUND 243 (0.059 g, 48%) asa white foam. ¹H NMR (CDCl₃) δ 0.98 (d+m, 4H), 1.16 (m, 1H), 1.30 (t+m,5H), 1.55 (m, 1H), 1.76 (m, 1H), 1.91 (m, 2H), 2.16 (brt, 1H), 2.36 (s,3H), 2.54 (s, 3H), 2.75-2.89 (m, 3H), 3.35 (m, 1H), 3.78 (m, 1H), 4.17(q, 2H, J=6.0 Hz), 7.01 (m, 1H), 7.11-7.15 (m, 3H), 7.32 (m, 1H); ES-MSm/z 586 (M+H).

Example 244

Compound 244(1-{(R)-3-[(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-carbamicacid 4-nitro-benzyl ester

A solution of6-chloro-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(52 mg, 0.12 mmol), 4-nitrobenzyl chloroformate (50 mg, 0.23 mmol) andDIPEA (50 μL, 0.29 mmol) in THF (0.90 ml) was stirred at 60° C. for 16hours. Once cooled, the reaction was diluted with saturated aqueousNaHCO₃ (25 ml) and was extracted with CH₂Cl₂ (20 ml×3). The combinedorganic solution was dried (Na₂SO₄), filtered and concentrated underreduced pressure. Purification by flash column chromatography on silica(CH₂Cl₂/MeOH, 29:1) gave COMPOUND 244 as an off-white foam (47.2 mg,64%). ¹H NMR (CDCl₃) δ 0.85-1.30 (m, 2H), 0.97 (d, 3H, J=7.0 Hz),1.48-1.81 (m, 4H), 2.05-2.17 (m, 1H), 2.31 (s, 3H), 2.43-2.57 (m, 1H),2.52 (s, 3H), 2.66-2.87 (m, 3H), 3.22-3.35 (m, 1H), 3.77-4.06 (m, 4H),5.17 (s, 2H), 6.93-7.05 (m, 3H), 7.20-7.32 (m, 3H), 8.13 (d, 2H, J=7.3Hz), 8.60 (br s, 1H); ES-MS m/z 614 (M+H), 616 (M+H+2).

Examples 245 to 258 were prepared following the scheme illustratedbelow. R¹ is as shown in the individual examples and R²—SMe is asdefined in the table.

TABLE 17

Example R²—SMe 245 S-methyl N-cyano-N′-methylcarbamimidothioate 246((methylamino)methylthiomethylene)methane- 1,1-dicarbonitrile 247N-methyl-1-(methylthio)-2-nitroethenamine 248 S-methylN-methanesulfonyl-N′-methyl- carbamimidothioate 249 S-methylN-nitro-N'-methyl- carbamimidothioate 2501-ethyl-2-methyl-3-cyanoisothiourea 2511-acetyl-2,3-dimethyl-isothiourea 2523-ethylamino-3-methylsulfanyl-acrylonitrile 2531-cyclopropyl-2-methyl-3-cyanoisothiourea 2541-isopropyl-2-methyl-3-cyanoisothiourea 2551-methoxyethyl-2-methyl-3-cyanoisothiourea 2561-cyclopropyl-2-methyl-3-cyanoisothiourea (see EXAMPLE 253) 2571-cyclopropyl-2-methyl-3-cyanoisothiourea (see EXAMPLE 253) 2581-cyclobutyl-2-methyl-3-cyanoisothiourea

Example 245

Compound 2456-Chloro-2,4-dimethyl-N—{(R)-3-[4-(N′-methyl-N-thiophen-3-ylmethyl-N″-cyanoguanidino)-piperidin-1-yl]-butyl}-nicotinamide

General Procedure for Formation of N-substituted Guanidines:

To a solution of6-chloro-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(82 mg, 0.14 mmol) in DMF (2 ml) was added S-methylN-cyano-N′-methylcarbamimidothioate (31 mg, 0.24 mmol), Et₃N (0.10 ml,0.72 mmol) and AgOTf (64 mg, 0.25 mmol) and the reaction stirred for 1h. The mixture was diluted with CH₂Cl₂ (25 ml) and saturated aqueousNaHCO₃ (25 ml) and the aqueous layer extracted with CH₂Cl₂ (2×10 ml).The combined organic extracts were dried (Na₂SO₄), concentrated andpurified by column chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH,96:4:0 then 9:1:0 then 88:10:2) to afford COMPOUND 245 (45 mg, 45%) as awhite foam. ¹H NMR (CDCl₃) δ 0.84-0.95 (m, 1H), 0.97-1.04 (m, 1H), 1.01(d, 3H, J=6.6 Hz), 1.50-1.77 (m, 4H), 2.13-2.21 (m, 1H), 2.29 (s, 3H),2.48 (s, 3H), 2.52-2.61 (m, 1H), 2.69-2.84 (m, 3H), 3.06 (d, 3H, J=4.8Hz), 3.21-3.30 (m, 1H), 3.71-3.91 (m, 3H), 4.26-4.35 (m, 1H), 4.72-4.77(m, 1H), 6.99 (s, 1H), 7.07 (d, 1H, J=4.8 Hz), 7.11 (br s, 1H), 7.42(dd, 1H, J=4.8, 3 Hz), 8.77 (br d, 1H); ¹³C NMR (CDCl₃) δ 13.92, 19.15,22.44, 30.19, 30.90, 31.02, 31.27, 40.51, 43.51, 51.96, 55.53, 60.97,117.54, 121.94, 122.87, 126.13, 128.28, 133.34, 137.93, 148.12, 150.37,155.77, 159.80, 167.27; ES-MS m/z 516 (M+H). Anal. Calcd. forC₂₅H₃₄N₇OSCl·1.0CH₂Cl₂·0.4H₂O: C, 51.34; H, 6.10; N, 16.12. Found: C,51.12; H, 5.95; N, 16.27.

Example 246

Compound 2462,6-Dichloro-N—((R)-3-{4-[(2,2-dicyano-1-methylamino-vinyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide

¹H NMR (CDCl₃+drop of CD₃OD) δ 0.80-0.85 (m, 1H), 1.05-1.22 (m, 5H),1.55-1.74 (m, 3H), 1.80-2.27 (m, 3H), 2.33 (s, 3H), 2.73 (br s, 3H),2.85-2.96 (m, 3H), 3.34-3.40 (m, 1H), 3.62-3.66 (m, 1H), 3.85-3.93 (m,1H), 4.05-4.16 (m, 1H), 6.81-6.84 (m, 1H), 7.08 (br s, 2H), 7.29-7.33(m, 1H); ES-MS m/z 560 (M+H). Anal. Calcd. forC₂₆H₃₁N₇OSCl₂·0.8CH₂Cl₂·1.7CH₃OH: C, 50.12; H, 5.81; N, 14.36. Found: C,50.30; H, 5.47; N, 14.04.

Example 247

Compound 2476-Chloro-2,4-dimethyl-N—((R)-3-{4-[(1-methylamino-2-nitro-vinyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-nicotinamide

¹H NMR (CDCl₃) δ 0.98 (d, 3H, J=7 Hz), 1.18-1.80 (m, 6H), 2.27 (t, 1H,J=12 Hz), 2.30 (s, 3H), 2.48-2.51 (m, 4H), 2.67-2.86 (m, 3H), 2.95 (d,3H, J=6 Hz), 3.14-3.37 (m, 2H), 3.73-3.85 (m, 1H), 3.87 (s, 2H), 6.53(s, 1H), 6.85 (dd, 1H, J=6, 3 Hz), 6.94 (s, 1H), 7.07 (br s, 1H), 7.28(dd, 1H, J=6, 3 Hz), 8.01 (br s, 1H), 9.68 (br s, 1H); ES-MS m/z 557(M+Na).

Example 248

Compound 2486-Chloro-2,4-dimethyl-N—{(R)-3-[4-(N′-methyl-N-thiophen-3-ylmethyl-N″-methanesulfonylguanidino)-piperidin-1-yl]-butyl}-nicotinamide

To a solution of methanesulfonamide (2.11 g, 22.2 mmol) in DMF (22 ml)was added 10 N NaOH (2.8 ml) and the reaction cooled to 0° C. beforeadding carbon disulfide (0.80 ml, 13.3 mmol). The mixture was stirredfor 15 min. before adding another portion of 10 N NaOH (1.3 ml) andcarbon disulfide (0.40 ml, 6.7 mmol). The reaction was stirred at 0° C.for another 30 min. before warming to room temperature and stirring for30 min. The reaction was cooled to 0° C., diluted with MeI (2.8 ml, 45.0mmol), allowed to warm to room temperature and stirred for 1.5 h. Themixture was then diluted with water (30 ml) and extracted with EtOAc(4×25 ml). The combined organic extracts were dried (Na₂SO₄) andconcentrated. The resultant crude product was washed with EtOAc/Hexanesto afford the desired N-methanesulfonylcarbonimidodithioic acid dimethylester (3.2 g, 77%) as a white solid. ¹H NMR (CDCl₃) δ 2.55 (s, 6H), 3.13(s, 3H).

To a solution of N-methanesulfonylcarbonimidodithioic acid dimethylester (1.5 g, 8.02 mmol) in MeOH (15 ml) was added a solution ofmethylamine in THF (2.0 M, 4.8 ml, 9.6 mmol) and the reaction heated to50° C. for 2.5 h before another portion of methylamine was added (4.8ml, 9.6 mmol) and the reaction heated to 50° C. for an additional 1 h.The mixture was concentrated and purified by column chromatography onsilica gel (EtOAc/Hexanes, 1:1) to afford S-methylN-methanesulfonyl-N′-methylcarbamimidothioate (0.95 g, 70%) as a clearoil. ¹H NMR (CDCl₃) δ 2.40 (s, 3H), 2.96 (d, 3H, J=6 Hz), 3.01 (s, 3H),7.95 (br s, 1H).

¹H NMR (CDCl₃) δ 0.99 (d, 3H, J=6.6 Hz), 1.05-1.34 (m, 2H), 1.51 1.82(m, 4H), 2.07-2.15 (m, 1H), 2.29 (s, 3H), 2.49 (s, 3H), 2.49-2.55 (m,1H), 2.66 (s, 3H), 2.75-2.87 (m, 3H), 2.90 (d, 3H, J=5.1 Hz), 3.27-3.34(m, 1H), 3.61-3.95 (m, 4H), 6.30-6.34 (m, 1H), 6.95 (s, 1H), 6.98 (dd,1H, J=4.8, 1.2 Hz), 7.09 (br s, 1H), 7.30 (dd, 1H, J=4.8, 3 Hz), 8.23(br s, 1H); ¹³C NMR (CDCl₃) δ 13.84, 19.14, 22.45, 30.22, 31.05, 31.51,32.50, 39.91, 42.64, 43.13, 44.11, 52.07, 57.82, 60.27, 121.93, 122.85,126.86, 126.92, 132.97, 139.31, 147.81, 150.56, 155.63, 160.74, 167.57;ES-MS m/z 591 (M+Na). Anal. Calcd. for C₂₅H₃₇N₆O₃S₂Cl·0.9CH₂Cl₂·0.1H₂O:C, 48.05; H, 6.07; N, 12.98. Found: C, 48.15; H, 6.08; N, 13.01.

Example 249

Compound 2492,6-Dichloro-4-methyl-N—{(R)-3-[4-(N′-methyl-N-thiophen-3-ylmethyl-N″-nitroguanidino)-piperidin-1-yl]-butyl}-nicotinamide

To a mixture of fuming nitric acid (10 ml) and concentrated sulfuricacid (20 ml) at −10° C. was added 2-methyl-2-thiopseudourea sulfate (2.5g, 9.0 mmol) in portions over a period of 15 min. The reaction waswarmed to 0° C. and another portion of 2-methyl-2-thiopseudourea sulfate(2.5 g, 9.0 mmol) was added. The mixture was stirred at 0° C. for 15min. then poured onto ice (300 g). The resultant white solid wasfiltered, washed with water and dried to give2-methyl-1-nitro-2-thiopseudourea (3.7 g). ¹H NMR (DMSO-d₆) δ 2.38 (s,3H), 9.11 (br s, 2H); ES-MS m/z 158 (M+Na).

To a solution of 2-methyl-1-nitro-2-thiopseudourea (430 mg, 3.19 mmol)in DMF (3 ml) was added Cs₂CO₃ (1.10 g, 3.38 mmol) and MeI (0.30 ml,4.82 mmol) and the reaction stirred overnight. The mixture was thendiluted with water (10 ml) and EtOAc (40 ml) and the organic layerwashed with brine (3×15 ml), dried (Na₂SO₄) and concentrated. Theresultant yellow oil was purified by column chromatography on silica gel(EtOAc/Hexanes, 1:1) to afford S-methylN-nitro-N′-methylcarbamimidothioate (56 mg, 11%) as a white solid. ¹HNMR (CDCl₃) δ 2.52 (s, 3H), 3.12 (d, 3H, J=6 Hz), 10.05 (br s, 1H).

¹H NMR (CDCl₃) δ 1.01 (d, 3H, J=6.6 Hz), 1.23-1.57 (m, 3H), 1.75-1.82(m, 3H), 2.25-2.32 (m, 1H), 2.32 (s, 3H), 2.53-2.60 (m, 1H), 2.74-2.92(m, 6H), 3.31-3.36 (m, 1H), 3.64-3.71 (m, 1H), 4.18-4.25 (m, 3H), 6.31(br s, 1H), 7.02 (d, 1H, J=4.8 Hz), 7.11 (s, 1H), 7.22 (br s, 1H), 7.37(dd, 1H, J=4.8, 3 Hz), 8.31 (br d, 1H); ¹³C NMR (CDCl₃) δ 14.00, 19.60,29.93, 30.30, 30.56, 31.18, 39.67, 43.80, 44.05, 51.11, 57.18, 59.97,122.66, 124.91, 126.28, 128.20, 132.79, 135.42, 146.83, 150.23, 151.55,161.34, 164.66; ES-MS m/z 578 (M+Na). Anal. Calcd. forC₂₃H₃₁N₇O₃SCl₂·1.3CH₂Cl₂: C, 43.76; H, 5.08; N, 14.70. Found: C, 43.67;H, 5.02; N, 14.75.

Example 250

Compound 2506-Chloro-N—{(R)-3-[4-(N′-ethyl-N-thiophen-3-ylmethyl-cyanoguanidino)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

General Procedure for the Formation of1-ethyl-2-methyl-3-cyanoisothiourea:

To a solution of dimethyl cyanodithioiminocarbonate (2.85 g, 17.6 mmol)in methanol (20 mL) was added ethylamine (2M soln, 9.7 mL, 19.4 mmol).The solution was allowed to stir at reflux overnight. The solution wascooled to room temperature and the desired product crystallized out ofsolution over 2 hours. The crystals were collected on a buchner funnel,washed with cold methanol several times, and dried in vacuo to give1-ethyl-2-methyl-3-cyanoisothiourea as a white solid (1.08 g, 43%). ¹HNMR (CDCl₃) δ 1.22 (t, 3H, J=6 Hz), 2.61 (s, 3H), 3.35 (s, 1H), 3.46 (q,2H, J=6 Hz).

¹H NMR (CDCl₃) δ 0.77-0.91 (m, 1H), 0.98-1.09 (m, 6H), 1.46-1.52 (m,2H), 1.64-1.78 (m, 3H), 2.13-2.24 (m, 1H), 2.28 (s, 3H), 2.48 (s, 3H),2.51-2.61 (m, 1H), 2.65-2.72 (m, 1H), 2.78-2.85 (m, 2H), 3.22-3.29 (m,1H), 3.48-3.55 (m, 2H), 3.77 (m, 2H), 3.87-3.94 (m, 1H), 4.27-4.32 (m,1H), 4.55-4.62 (m, 1H), 6.95 (s, 1H), 7.04 (d, 1H, J=6 Hz), 7.14 (s,1H), 7.40-7.44 (m, 1H), 8.76 (br s, 1H); ES-MS m/z 530 (M+H).

Example 251

Compound 2516-Chloro-2,4-dimethyl-N—{(R)-3-[4-(N′-methyl-N-thiophen-3-ylmethyl-N′-acetylguanidino)-piperidin-1-yl]-butyl}-nicotinamide

To a suspension of 1-methyl-2-thiurea (2.12 g, 23.5 mmol) in MeOH (10ml) was added MeI (1.60 ml, 25.7 mmol) and the reaction stirred for 1 h.The mixture was then concentrated to afford a white solid (5.55 g). To asolution of the solid from above (0.72 g) in THF (20 ml) was added Et₃N(2.0 ml, 14.3 mmol) and acetyl chloride (0.5 ml, 7.03 mmol) and theresulting suspension stirred at room temperature for 3.5 h. The mixturewas diluted with CH₂Cl₂ (40 ml) and saturated aqueous NaHCO₃ (25 ml) andthe organic extract washed with brine (1×25 ml), dried (Na₂SO₄),concentrated and purified by column chromatography on silica gel(EtOAc/Hexanes, 1:2 then 1:1) to afford1,1-diacetyl-2,3-dimethyl-isothiourea (0.17 g, 29%) as a clear oil. ¹HNMR (CDCl₃) δ 2.17 (s, 3H), 2.18 (s, 3H), 2.37 (s, 3H), 3.13 (s, 3H).

To a solution of 1,1-diacetyl-2,3-dimethyl-isothiourea (0.17 g, 0.90mmol) in MeOH (10 ml) was added K₂CO₃ (250 mg, 1.81 mmol) and thereaction stirred at room temperature for 1.5 h. The mixture wasconcentrated, diluted with CH₂Cl₂ (25 ml) and water (20 ml) and theaqueous layer was extracted with CH₂Cl₂ (2×10 ml), dried (Na₂SO₄) andconcentrated to afford 1-acetyl-2,3-dimethyl-isothiourea (112 mg, 85%)as a white solid. ¹H NMR (CDCl₃) δ 2.10 (s, 3H), 2.43 (s, 3H), 2.93 (s,3H).

¹H NMR (CDCl₃) δ 0.81-0.93 (m, 1H), 0.93-1.05 (m, 1H), 0.97 (d, 3H,J=6.6 Hz), 1.47-1.53 (m, 1H), 1.64-1.77 (m, 4H), 2.07 (s, 3H), 2.00-2.14(m, 1H), 2.28 (s, 3H), 2.47 (s, 3H), 2.47-2.55 (m, 1H), 2.67-2.82 (m,3H), 2.76 (d, 3H, J=4.2 Hz), 3.18-3.28 (m, 1H), 3.78-3.93 (m, 3H),4.19-4.26 (m, 1H), 5.38-5.42 (m, 1H), 6.99 (s, 1H), 7.11 (dd, 1H, J=5.1,1.2 Hz), 7.23 (br s, 1H), 7.37 (dd, 1H, J=5.1, 3 Hz), 8.74 (br d, 1H);¹³C NMR (CDCl₃) δ 13.87, 19.09, 22.40, 26.42, 30.21, 30.43, 30.94,31.24, 40.48, 42.68, 43.64, 52.14, 55.81, 60.92, 122.28, 122.91, 126.41,127.71, 133.27, 137.09, 148.06, 150.42, 155.72, 163.87, 167.29, 175.23;ES-MS m/z 555 (M+Na). Anal. Calcd. for C₂₆H₃₇N₆O₂SCl·1.2CH₂Cl₂: C,51.44; H, 6.25; N, 13.23. Found: C, 51.30; H, 6.14; N, 13.42.

Example 252

Compound 2526-Chloro-N—((R)-3-{4-[(2-cyano-1-ethylamino-vinyl)-thiophen-3-ylmethyl-amino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

To a solution of distilled acetonitrile (1.0 ml, 19.1 mmol) in THF (20ml) at −78° C. was added a solution of n-butyl lithium in hexanes (2.1M, 9.0 ml, 18.9 mmol) and the mixture stirred at −78° C. for 30 min.before adding ethyl isothiocyanate (0.56 ml, 6.39 mmol). The mixture wasstirred at −78° C. for 10 min. then at 0° C. (ice bath) for 30 min.before quenching with water (20 ml). The organic phase was washed withwater (2×15 ml) and the combined aqueous layers washed with hexanes(1×25 ml). To the combined aqueous layers was added MeI (0.80 ml, 12.9mmol) and the mixture stirred at room temperature for 2.5 h. Thereaction was extracted with EtOAc (3×25 ml) and the organic extractsdried (Na₂SO₄), concentrated and purified by column chromatography(Hexanes/EtOAc, 9:1 then 3:1) to afford3-ethylamino-3-methylsulfanyl-acrylonitrile (0.85 g, 94%) as a paleyellow oil and mixture of E/Z regioisomers (˜2:1). ¹H NMR (CDCl₃) δ1.20-1.29 (m, total 3H), 2.33 (s, 1.1H), 2.50 (s, 1.9H), 3.03-3.12 (m,1.3H), 3.36-3.41 (m, 0.7H), 3.65 (s, 0.3H), 4.11 (s, 0.7H), 4.38 (br s,0.7H), 4.90 (br s, 0.3H).

1:1 Mixture of E/Z regioisomers: ¹H NMR (CDCl₃) δ 0.91-1.15 (m, 8H),1.48-1.55 (m, 1H), 1.66-1.76 (m, 2H), 1.86-1.93 (m, 1H), 2.04-2.20 (m,1H), 2.28 (s) and 2.29 (s) (total 3H), 2.46-2.59 (m, 1H), 2.49 (s, 3H),2.70-2.86 (m, 3H), 3.18-3.28 (m, 2H), 3.37-3.48 (m, 1H), 3.71-3.84 (m,5H), 6.95-6.97 (m) and 7.00-7.05 (m) and 7.10 (br s) (total 3H),7.29-7.32 (m, 1H), 8.39 (br d) and 8.87 (br d) (total 1H); ES-MS m/z 529(M+H).

Example 253

Compound 2536-Chloro-N—{(R)-3-[4-(N′-cyclopropyl-N-thiophen-3-ylmethyl-cyanoguanidino)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

1-Cyclopropyl-2-methyl-3-cyanoisothiourea was prepared following thesame procedure as for 1-ethyl-2-methyl-3-cyanoisothiourea (see EXAMPLE250) except cyclopropylamine was used in lieu of ethylamine. ¹H NMR(CDCl₃) δ 0.66-0.76 (m, 2H), 0.83-0.92 (m, 2H), 2.43 (s, 3H), 2.64 (brs, 1H), 6.78 (br s, 1H).

¹H NMR (CDCl₃) δ 0.34-0.39 (m, 2H), 0.80-0.89 (m, 3H), 0.98 (d, 3H, J=6Hz), 0.98-1.09 (m, 1H), 1.47-1.53 (m, 1H), 1.64-1.75 (m, 3H), 2.13-2.24(m, 1H), 2.27 (s, 3H), 2.47 (s, 3H), 2.52-2.62 (m, 1H), 2.64-2.74 (m,1H), 2.78-2.86 (m, 2H), 2.88-2.94 (m, 1H), 3.20-3.28 (m, 1H), 3.71 (s,2H), 3.78-3.84 (m, 1H), 4.25-4.32 (m, 1H), 5.02 (s, 1H), 6.92 (s, 1H),6.96-7.00 (d, 1H, J=6 Hz), 7.09 (s, 1H), 7.39-7.43 (m, 1H), 8.72 (br s,1H); ES-MS m/z 542 (M+H).

Example 254

Compound 2546-Chloro-N—{(R)-3-[4-(N′-isopropyl-N-thiophen-3-ylmethyl-cyanoguanidino)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

1-Isopropyl-2-methyl-3-cyanoisothiourea was prepared following the sameprocedure as for 1-ethyl-2-methyl-3-cyanoisothiourea (see EXAMPLE 250)except isopropylamine was used in lieu of ethylamine. ¹H NMR (CDCl₃) δ1.25 (d, 6H, J=6 Hz), 2.49 (br s, 3H), 3.84 (br s, 1H), 6.22 (br s, 1H).

¹H NMR (CDCl₃) δ 0.80-0.89 (m, 1H), 0.92-0.99 (m, 9H), 0.99-1.09 (m,1H), 1.48-1.53 (m, 1H), 1.64-1.77 (m, 3H), 2.14-2.24 (m, 1H), 2.27 (s,3H), 2.48 (s, 3H), 2.54-2.63 (m, 1H), 2.73-2.82 (m, 3H), 3.19-3.27 (m,1H), 3.76 (s, 2H), 3.77-3.84 (m, 1H), 4.25-4.44 (m, 3H), 6.92 (s, 1H),6.99-7.04 (d, 1H, J=6 Hz), 7.14 (s, 1H), 7.39-7.43 (m, 1H), 8.71 (br s,1H); ES-MS m/z 544 (M+H).

Example 255

Compound 2556-Chloro-N—((R)-3-{4-[N-(2-methoxy-ethyl)-N-thiophen-3-ylmethyl-cyanoguanidino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

1-Methoxyethyl-2-methyl-3-cyanoisothiourea was prepared following thesame procedure as for 1-ethyl-2-methyl-3-cyanoisothiourea (see EXAMPLE250) except methoxyethylamine was used in lieu of ethylamine. ¹H NMR(CDCl₃) δ 2.53 (br s, 3H), 3.37 (s, 3H), 3.52 (m, 4H), 6.29 (br s, 1H).

¹H NMR (CDCl₃) δ 0.79-0.91 (m, 1H), 0.99 (d, 3H, J=6 Hz), 1.00-1.09 (m,1H), 1.47-1.52 (m, 1H), 1.62-1.74 (m, 3H), 2.13-2.23 (m, 1H), 2.28 (s,3H), 2.48 (s, 3H), 2.53-2.63 (m, 1H), 2.64-2.74 (m, 1H), 2.78-2.86 (m,2H), 3.20 (m, 3H), 3.21-3.27 (m, 1H), 3.34 (t, 2H, J=6 Hz), 3.61-3.67(m, 2H), 3.78 (br s, 2H), 3.79-3.92 (m, 1H), 4.22-4.27 (m, 1H),5.17-5.23 (m, 1H), 6.93 (s, 1H), 7.02 (d, 1H, J=6 Hz), 7.14 (s, 1H),7.36-7.43 (m, 1H), 8.72 (br s, 1H); ES-MS m/z 582 (M+Na).

Example 256

Compound 256N—{(R)-3-[4-(N′-Cyclopropyl-N-thiophen-3-ylmethyl-cyanoguanidino)-piperidin-1-yl]-butyl}-6-fluoro-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.30-0.35 (m, 2H), 0.75-0.89 (m, 3H), 1.00 (d, 3H, J=6Hz), 1.00-1.09 (m, 1H), 1.49-1.57 (m, 1H), 1.72-1.84 (m, 3H), 2.14-2.23(m, 1H), 2.29 (s, 3H), 2.44 (s, 3H), 2.53-2.61 (m, 1H), 2.69-2.92 (m,4H), 3.21-3.28 (m, 1H), 3.70 (s, 2H), 3.78-3.85 (m, 1H), 4.27-4.38 (m,1H), 5.05 (s, 1H), 6.41 (s, 1H), 6.89 (d, 1H, J=3 Hz), 7.04 (s, 1H),7.38-7.43 (m, 1H), 8.65 (br s, 1H); ES-MS m/z 526 (M+H).

Example 257

Compound 2576-Cyano-N—{(R)-3-[4-(N′-cyclopropyl-N-thiophen-3-ylmethyl-cyanoguanidino)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

¹H NMR (CDCl₃) δ 0.30-0.37 (m, 2H), 0.80-0.91 (m, 3H), 0.95-1.08 (m,4H), 1.46-1.57 (m, 1H), 1.70-1.77 (m, 3H), 2.16-2.24 (m, 1H), 2.33 (s,3H), 2.54 (s, 3H), 2.54-2.65 (m, 1H), 2.69-2.97 (m, 4H), 3.17-3.24 (m,1H), 3.70 (s, 2H), 3.79-3.85 (m, 1H), 4.26-4.37 (m, 1H), 5.02 (s, 1H),6.94 (d, 1H, J=6 Hz), 7.12 (br s, 1H), 7.22 (s, 1H), 7.42-7.47 (m, 1H),8.70 (br s, 1H).

Example 258

Compound 258N—{(R)-3-[4-(N′-Cyclobutyl-N-thiophen-3-ylmethyl-cyanoguanidino)-piperidin-1-yl]-butyl}-6-fluoro-2,4-dimethyl-nicotinamide

1-Cyclobutyl-2-methyl-3-cyanoisothiourea was prepared following the sameprocedure as for 1-ethyl-2-methyl-3-cyanoisothiourea (see EXAMPLE 250)except that cyclobutylamine was used in lieu of ethylamine. ¹H NMR(CDCl₃) δ 1.62-1.79 (m, 2H), 1.92-2.08 (m, 2H), 2.29-2.45 (m, 5H), 4.11(br s, 1H), 6.74 (br s, 1H).

¹H NMR (CDCl₃) δ 0.78-0.90 (m, 1H), 0.99 (d, 3H, J=6 Hz), 0.99-1.09 (m,1H), 1.47-1.62 (m, 5H), 1.63-1.81 (m, 3H), 2.14-2.22 (m, 1H), 2.31 (s,3H), 2.31-2.40 (m, 2H), 2.45 (s, 3H), 2.54-2.63 (m, 1H), 2.72-2.86 (m,3H), 3.21-3.29 (m, 1H), 3.74 (s, 2H), 3.81-3.90 (m, 1H), 4.24-4.32 (m,1H), 4.44-4.52 (m, 1H), 4.80 (m, 1H), 6.42 (s, 1H), 6.94-6.98 (m, 1H),7.12 (br s, 1H), 7.40-7.47 (m, 1H), 8.72 (br s, 1H); ES-MS m/z 562(M+Na).

Example 259

Compound 2596-Chloro-2,4-dimethyl-N—{(R)-3-[4-(N-thiophen-3-ylmethyl-N″-cyanoguanidino)-piperidin-1-yl]-butyl}-nicotinamide

To a stirred solution of6-chloro-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide(100 mg, 0.23 mmol) in 1-butanol (5 ml) was added solid sodiumdicyanamide (41 mg, 0.46 mmol) followed by a 4.0 M HCl/dioxane solution(0.12 ml, 0.46 mmol). The resulting solution was heated to reflux (120°C.) for 2 h, then cooled to rt. Saturated aqueous NaHCO₃ (10 ml) wasadded, and the mixture was extracted with CH₂Cl₂ (3×20 ml). The combinedorganic extracts were dried (MgSO₄) and concentrated, then purified byflash chromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 20:2:1) to giveCOMPOUND 259 as a white foam (85 mg, 74%). ¹H NMR (CDCl₃) δ 0.89-1.10(m, 4H), 1.50-1.74 (m, 5H), 2.16 (t, 1H, J=12 Hz), 2.28 (s, 3H), 2.47(s, 3H), 2.55 (t, 1H, J=9 Hz), 2.69-2.83 (m, 3H), 3.24-3.31 (m, 1H),3.81-3.89 (m, 3H), 4.22-4.27 (m, 1H), 5.29 (br s, 2H), 6.97 (s, 1H),7.04 (d, 1H, J=6 Hz), 7.13 (br s, 1H), 7.39 (dd, 1H, J=6, 3 Hz), 8.60(br s, 1H); ES-MS m/z 524 (M+Na).

Example 260

Compound 2602,6-Dimethyl-N-{3-[4-((R)-4-phenyl-2-thioxo-oxazolidin-3-yl)-piperidin-1-yl]-butyl}-4-pyridin-4-yl-benzamide

Using general procedure A, R-(−)-2-phenylglycinyl (91 mg, 0.66 mmol) and[3-(4-oxopiperidin-1-yl)butyl]-carbamic acid tert-butyl ester (225 mg,0.834 mmol) provided{3-[4-(2-hydroxy-1-phenylethylamino)piperidin-1-yl]butyl}carbamic acidtert-butyl ester as a colorless foam (177 mg, 68%).

The above carbamate (159 mg, 0.407 mmol) was dissolved in CH₂Cl₂ (4 ml)and then cooled to 0° C. Trifluoroacetic acid (2.0 ml, 26 mmol) wasadded dropwise to the cooled solution and then the reaction was allowedto stir for 10 minutes at 0° C., and then 30 minutes at roomtemperature. The solution was concentrated and the residue dissolved in9:1 CH₂Cl₂/MeOH (10 ml). mgSO₄ was added and the reaction mixturestirred for 30 minutes, then potassium carbonate (373 mg, 2.70 mmol) wasadded and the solution was concentrated to afford2-[1-(3-amino-1-methylpropyl)piperidin-4-ylamino]-2-phenylethanol as alight yellow oil (106 mg, 89%) following purification.

Using general procedure E, the above amine (59 mg, 0.20 mmol) and2,6-dimethyl-4-pyridin-4-ylbenzoic acid (60 mg, 0.27 mmol) gaveN-{3-[4-(2-hydroxy-1-phenylethylamino)piperidin-1-yl]butyl}-2,6-dimethyl-4-pyridin-4-ylbenzamideas a light yellow foam (66 mg, 65%).

The above diamine (65 mg, 0.13 mmol) and thiocarbonyldiimidazole (26 mg,0.15 mmol) in DMF (0.3 ml) were stirred at room temperature for 18hours. The solution was concentrated under high vacuum and the residuewas dissolved in EtOAc (35 ml) and distilled water (2.5 ml). Aqueouswork-up and purification afforded COMPOUND 260 as a light yellow foam(33 mg, 46%). ¹H NMR (CDCl₃) δ 0.77-0.97 (m, 9H), 1.10-2.91 (m, 32H),3.24 (m, 1H), 3.41 (m, 1H), 3.59 (m, 1H), 3.87-4.48 (m, 10H), 7.07 (m,4H), 7.26-7.49 (m, 14H), 8.64 (m, 4H); ¹³C NMR (CDCl₃) δ 13.24, 13.71,19.41, 28.86, 29.62, 30.41, 31.22, 31.45, 32.28, 39.00, 43.48, 44.09,51.00, 51.32, 53.46, 56.69, 58.80, 59.67, 60.54, 60.78, 28.86, 29.62,30.41, 31.22, 31.45, 32.28, 39.00, 43.48, 44.09, 51.00, 51.32, 53.46,56.69, 58.80, 59.67, 60.54, 60.78, 74.75, 121.17, 121.28, 126.03,126.10, 129.12, 129.37, 135.47, 135.55, 137.98, 138.06, 139.14, 139.33,140.08, 140.17, 147.15, 147.34, 150.41, 150.46, 168.97, 169.57, 187.17;ES-MS m/z 543 (M+H). Anal. Calcd. for C₃₂H₃₈N₄O₂S·0.75CH₄O·0.1CH₂Cl₂: C,68.59; H, 7.22; N, 9.74; S, 5.57. Found: C, 68.95; H, 7.08; N, 9.68; S,5.55.

Example 261

Compound 2616-Cyano-2,4-dimethyl-N-{3-[4-((R)-4-phenyl-2-thioxo-oxazolidin-3-yl)-piperidin-1-yl]-butyl}-nicotinamide

Using general procedure E,(R)-3-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-4-phenyl-oxazolidine-2-thione(31 mg, 0.093 mmol) and 6-cyano-2,4-dimethylnicotinic acid (21 mg, 0.12mmol) gave COMPOUND 261 as a beige foam (42.6 mg, 93%). ¹H NMR (CDCl₃) δ0.73-1.10 (m, 2H), 0.94 and 0.95 (d, 3H, J=6.6 Hz), 1.16-1.78 (m, 4H),1.87-1.96 (m, 1H), 2.18 and 2.18 (td, 1H, J=11.7, 2.2 Hz), 2.33-2.81 (m,3H), 2.38 and 2.39 (s, 3H), 2.58 and 2.59 (s, 3H), 3.22-3.85 (m, 2H),4.15-4.29 (m, 1H), 4.30 and 4.31 (d, 1H, J=8.8 Hz), 4.48 and 4.58 (dd,1H, J=8.9, 3.4 Hz), 4.68 and 4.71 (dd, 1H, J=9.0, 5.4 Hz), 7.17-7.23 (m,2H), 7.33-7.44 (m, 3H), 7.46 and 7.47 (s, 1H), 7.67 and 7.75 (br s, 1H).ES-MS m/z 492 (M+H).

Example 262

Compound 2626-Chloro-2,4-dimethyl-N-{3-[4-((R)-4-phenyl-2-thioxo-oxazolidin-3-yl)-piperidin-1-yl]-butyl}-nicotinamide

Using general procedure E,(R)-3-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-4-phenyl-oxazolidine-2-thione(31 mg, 0.093 mmol) and 6-chloro-2,4-dimethylnicotinic acid (24 mg, 0.13mmol) gave COMPOUND 262 as a light yellow foam (37.1 mg, 80%). ¹H NMR(CDCl₃) δ 0.63-1.09 (m, 2H), 0.93 and 0.95 (d, 3H, J=6.6 Hz), 1.21-2.04(m, 5H), 2.18 and 2.37 (td, 1H, J=11.9, 2.2 Hz), 2.33 and 2.34 (s, 3H),2.50-2.83 (m, 3H), 2.53 and 2.55 (s, 3H), 3.12-3.22 and 3.59-3.68 (m,1H), 3.30-3.40 and 3.86-3.96 (m, 1H), 4.20-4.30 (m, 2H), 4.33 and 4.47(dd, 1H, J=8.6, 3.1 Hz), 4.66 and 4.69 (dd, 1H, J=8.6, 4.0 Hz), 7.12 and7.13 (s, 1H), 7.18-7.24 (m, 2H), 7.34-7.42 (m, 3H), 8.18 and 8.29 (br s,1H). ES-MS m/z 501 (M+H).

Example 263

Compound 2632,6-Dimethyl-N-{3-[4-((R)-2-oxo-4-phenyl-oxazolidin-3-yl)-piperidin-1-yl]-butyl}-benzamide

Using general procedure A, R-(−)-2-phenylglycinyl (250 mg, 1.82 mmol)and N-Boc-piperidone (400 mg, 2.0 mmol) gave the desired secondaryamine. The crude amine was treated with triphosgene (83 mg, 0.28 mmol)and pyridine (136 μL, 1.68 mmol) in CH₂Cl₂ to give the oxazolidinone.Using general procedure C, the crude oxazolidinone gave(R)-4-phenyl-3-piperidin-4-yl-oxazolidin-2-one (118 mg, 57% over 3steps).

Using general procedure B with the above amine (101 mg, 0.41 mmol) and2-(3-oxo-butyl)-isoindole-1,3-dione (179 mg, 0.82 mmol) followed bygeneral procedure D gave(R)-3-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-4-phenyl-oxazolidin-2-one(81 mg, 62% over 2 steps).

Using general procedure E with the above amine (48 mg, 0.16 mmol) and2,6-dimethylbenzoic acid (26 mg, 0.18 mmol) gave COMPOUND 263(57 mg,81%). ¹H NMR (CDCl₃) (mixture of diastereoisomer) δ 0.81-1.03 (m, 4H),1.04-2.80 (m, 10H), 2.34 (s, 3H), 2.36 (s, 3H), 3.12-4.45 (m, 6H),7.09-7.55 (m, 9H); ¹³C NMR (CDCl₃) δ 13.03, 13.60, 19.23, 29.10, 30.01,30.58, 31.37, 31.56, 32.31, 39.05, 43.23, 44.06, 51.15, 51.66, 52.69,57.08, 57.57, 58.94, 59.98, 70.68, 126.29, 127.51, 128.31, 128.70,129.14, 134.35; ES-MS m/z 450 (M+H). Anal Calcd. forC₂₇H₃₅N₃O₃·0.1CH₂Cl₂: C, 71.06; H, 7.74; N, 9.17. Found: C, 71.44; H,7.80; N, 9.09.

Example 264

Compound 2646-Chloro-2,4-dimethyl-N-{3-[4-((R)-2-oxo-5-phenyl-3-(2-methylpropyl)-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-nicotinamide

Using general procedure A, ((R)-2-amino-1-phenyl-ethyl)-carbamic acidtert-butyl ester (472 mg, 2.00 mmol) and 2-methylpropionaldehyde (181μL, 2.00 mmol) afforded((R)-2-(2-methylpropyl)amino-1-phenyl-ethyl)-carbamic acid tert-butylester (533 mg, 91%).

Using general procedure C,((R)-2-(2-methylpropyl)amino-1-phenyl-ethyl)-carbamic acid tert-butylester (533 mg, 1.83 mmol) afforded(R)—N²-(2-methylpropyl)-1-phenyl-ethane-1,2-diamine (350 mg, 99%).

Using general procedure A, (R)—N²-(2-methylpropyl)-1-phenyl-ethane-1,2-diamine (350 mg, 1.82 mmol) and[3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester (493 mg,1.83 mmol) afforded{3-[4-((R)-2-(2-methylpropyl)amino-1-phenyl-ethylamino)-piperidin-1-yl]-butyl}-carbamicacid tert-butyl ester (473 mg, 58%).

The diamine product was then dissolved in 4 ml of DCM. Pyridine (170 μL,168 mg, 2.12 mmol) was added and the mixture was cooled to 0° C.Thiophosgene (85 μL, 128 mg, 1.11 mmol) was added slowly to the stirringsolution. The reaction was allowed to warm up to room temperature withstirring for two hours. The reaction was then quenched by the additionof 50 ml of a saturated solution of NaHCO₃. Standard workup andpurification by flash column chromatography gave{3-[4-((R)-3-(2-methylpropyl)-2-thioxo-5-phenyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-carbamicacid tert-butyl ester (270 mg, 52%).

Using general procedure C with the above carbamate, and subsequentlygeneral procedure E with the resulting amine (44 mg, 0.113 mmol) and6-chloro-2,4-dimethylnicotinic acid (25 mg, 0.113 mmol) affordedCOMPOUND 264 as an off-white foam (40 mg, 64%). ¹H NMR (CDCl₃) δ 0.67(m, 1H), 0.87-0.95 (m, 9H), 1.31 (m, 1H), 1.52 (m, 1H), 1.61 (s, 3H),1.68 (m, 1H), 1.87-1.98 (m, 3H), 2.23 (m, 1H), 2.34 (d, 3H, J=4.5 Hz),2.55 (d, 3H, J=7.8 Hz), 2.64 (m, 1H), 2.73 (m, 1H), 3.10 (m, 2H), 3.33(m, 2H), 3.62 (m, 1H), 3.73-3.85 (m, 2H), 4.03 (m, 1H), 4.48 (m, 1H),7.13 (s, 1H), 7.19 (t, 2H, J=6.3 Hz), 7.29-7.37 (m, 4H), 8.56-8.82 (m,1H); ¹³C NMR (CDCl₃) δ 13.10, 13.62, 18.82, 19.92, 20.11, 22.18, 27.02,29.95, 31.24, 39.79, 43.03, 43.79, 51.51, 51.88, 54.67, 57.19, 57.62,57.71, 59.94, 60.74, 122.55, 125.60, 128.19, 129.03, 133.02, 142.92,147.80, 148.00, 150.03, 155.47, 155.52, 166.68, 167.41, 182.46; ES-MSm/z 556 (M+H), 578 (M+Na). Anal. Calcd. for C₃₀H₄₂N₅OSCl·0.2 (CH₂Cl₂):C, 63.28; H, 7.46; N, 12.22. Found: C, 63.18; H, 7.53; N, 12.18.

Examples 265 to 272 were prepared following similar chemistry.

Example 265

Compound 2656-Chloro-N-(3-{4-[(R)-3-(3-methoxy-2,2-dimethyl-propyl)-2-oxo-5-phenyl-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

3-Methoxy-2,2-dimethyl-propionaldehyde (Effenberger, F. et al.;Tetrahedron. Asymmetry; 6; 1995; 271-282) was used in lieu of2-methylpropionaldehyde. Mixture of diastereoisomers: ¹H NMR (CDCl₃) δ0.65-1.16 (m, 1H), 1.17-2.12 (m, 8H), 2.14-3.83 (m, 10H), 2.32 and 2.33(s, 3H), 2.51 and 2.53 (s, 3H), 3.20 (s, 3H), 3.95-4.0 and 4.05-4.15 (m,1H), 7.12 (s, 1H), 7.25-7.39 (m, 5H), 8.25 and 8.44 (s, 1H); ES-MS m/z584 (M+H).

Example 266

Compound 2666-Chloro-2,4-dimethyl-N-{3-[4-((R)-2-oxo-5-phenyl-3-(2-cyclopentyl)-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-nicotinamide

Cyclopentanone was used in lieu of 2-methylpropionaldehyde. COMPOUND 266was isolated as a white foam. ¹H NMR (CDCl₃) δ 0.78-0.94 (m, 4H),1.25-1.93 (m, 15H), 2.09 (m, 1H), 2.33 (d, 3H, J=4.2 Hz), 2.49 (m, 1H),2.53 (d, 3H, J=7.2 Hz), 2.64-2.71 (m, 2H), 2.96 (m, 1H), 3.13-3.36 (m,1H), 3.51-3.60 (m, 1H), 3.65 (t, 2H, J=9.0 Hz), 3.94-4.15 (m, 1H), 4.31(m, 1H), 7.12 (d, 1H, J=2.7 Hz), 7.22-7.36 (m, 5H), 8.13-8.33 (m, 1H);¹³C NMR (CDCl₃) δ 13.01, 13.53, 18.83, 22.15, 24.06, 24.16, 28.46,28.55, 28.91, 29.98, 30.52, 31.66, 39.60, 39.80, 43.24, 44.00, 48.67,51.67, 51.83, 52.13, 53.48, 55.05, 55.31, 59.66, 60.37, 122.62, 126.16,127.90, 128.77, 132.70, 132.83, 143.47, 143.67, 147.61, 147.75, 150.10,155.37, 160.27, 166.89, 167.49; ES-MS m/z 552 (M+H), 574 (M+Na). Anal.Calcd. for C₃₁H₄₂N₅O₂Cl 0.1CH₂Cl₂: C, 66.63; H, 7.59; N, 12.49. Found:C, 66.85; H, 7.70; N, 12.44.

Example 267

Compound 2676-Chloro-N-{3-[4-((R)-3-cyclobutyl-2-oxo-5-phenyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

Cyclobutanone was used in lieu of 2-methylpropionaldehyde. COMPOUND 267was isolated as a white foam. ¹H NMR (CDCl₃) δ 0.73-2.22 (m, 19H), 2.34(s, 3H), 2.50 (double s, 3H), 2.61-4.57 (m, 8H), 7.09 (s, 1H), 7.18-7.45(m, 5H), 7.95-8.31 (m, 1H); ¹³C NMR (CDCl₃) δ 11.36, 11.67, 13.18,17.24, 17.30, 20.56, 25.52, 25.57, 26.85, 28.06, 29.22, 30.00, 37.46,41.89, 42.60, 45.79, 47.40, 49.67, 49.96, 50.34, 53.43, 53.64, 57.84,58.49, 121.00, 124.73, 126.45, 127.20, 131.00, 141.66, 146.04, 148.48,153.71, 157.89, 165.51, 166.09; ES-MS m/z 539 (M+2). Anal. Calcd. forC₃₀H₄₀N₅ClO₂·0.7CH₂Cl₂: C, 61.70; H, 6.98; N, 11.72. Found: C, 61.89; H,7.02; N, 11.51.

Example 268

Compound 2686-Fluoro-N-{3-[4-((R)-3-cyclobutyl-2-oxo-5-phenyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

Cyclobutanone was used in lieu of 2-methylpropionaldehyde. COMPOUND 268was isolated as a white foam. ¹H NMR (CDCl₃) δ 0.70-2.18 (m, 19H), 2.32(s, 3H), 2.51 (double s, 3H), 2.59-4.55 (m, 8H), 7.09 (s, 1H), 7.18-7.36(m, 5H), 7.93-8.31 (m, 1H); ¹³C NMR (CDCl₃) δ 11.36, 11.67, 13.18,17.24, 17.30, 20.56, 25.52, 25.57, 26.85, 28.06, 29.22, 30.00, 37.46,41.89, 42.60, 45.79, 47.40, 49.67, 49.96, 50.34, 53.43, 53.64, 57.84,58.49, 121.00, 124.73, 126.45, 127.20, 131.00, 141.66, 146.04, 148.48,153.71, 157.89, 165.51, 166.09; ES-MS m/z 522 (M+H).

Example 269

Compound 2696-Chloro-N-{3-[4-(1′-cyclohexyl-1-methyl-2′-oxo-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-yl)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

To a solution of NH₄Cl (1.07 g, 20.0 mmol) and NaCN (0.980 g, 20.0 mmol)in ammonium hydroxide (10 ml) was added a solution of1-methyl-1H-imidazole-2-carbaldehyde (1.10 g, 10.0 mmol) in methanol (5ml). The mixture was stirred at room temperature for 4 h. The mixturewas diluted with water (20 ml), extracted with CH₂Cl₂-i-PrOH (4:1, v/v,4×40 ml). The combined organic extracts were dried (Na₂SO₄) andconcentrated to give a yellow oil. This was taken into CH₂Cl₂ (10 ml),Boc₂O (1.90 g) and triethylamine (1.5 ml) were added. The mixture wasstirred at room temperature for 4 h. Solvents were evaporated underreduced pressure. The residue was dissolved in methanol (20 ml),saturated with ammonia, Raney nickel (ca. 1 g) was added and the mixturewas hydrogenated at 45 psi for 5 h. The catalyst was removed byfiltration through a layer of Celite®. Solvents were evaporated underreduced pressure to give the crude product. This was purified by columnchromatography on silica gel, eluted with CH₂Cl₂—MeOH—NH₄OH (94:4:2) togive 2-amino-1-(1-methyl-1H-imidazol-2-yl)-ethyl]-carbamic acidtert-butyl ester (192 mg, 8%).

Cyclohexanone was used in lieu of 2-methylpropionaldehyde. COMPOUND 269was isolated as a white foam. ¹H NMR (CDCl₃) δ 0.98-1.41 (m, 12H),1.63-2.00 (m, 12H), 2.32, and 2.33 (double s, 3H), 2.50 (s, 3H),2.64-2.74 (m, 2H), 2.91 (br s, 2H), 3.31-3.78 (m, 7H), 4.69-4.82 (m,1H), 6.80 (s, 1H), 6.86-6.92 (m, 1H), 7.07 (d, 1H, J=4.8 Hz), 7.47 (brs, 1H); ES-MS m/z 571 (M+H).

Example 270

Compound 2706-[(R)-3-(1-{3-[(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-2-oxo-4-phenyl-imidazolidin-1-ylmethyl]-nicotinicacid

Methyl 4-formylbenzoate was used in lieu of 2-methylpropionaldehyde.Hydrolysis of the methyl ester using standard conditions affordedCOMPOUND 270. ¹H NMR (CD₃OD) δ 1.26-1.25 (m, 4H), 1.95-2.20 (m, 6H),2.28-2.80 (m, 4H), 2.29 (s, 3H), 2.30-2.50 (m, 4H), 3.00-3.10 (m, 3H),3.20-3.75 (m, 16H, CH₃OH signal), 4.41 (d, 1H, J=15.3 Hz)), 4.52 (d, 1H,J=15.3 Hz), 7.21-7.35 (m, 8H), 7.93 (d, 2H, J=7.2 Hz); ES-MS m/z 618(M+1).

Example 271

Compound 2715-[(R)-3-(1-{3-[(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-2-oxo-4-phenyl-imidazolidin-1-ylmethyl]-thiophene-2-carboxylicacid

5-Formyl-thiophene-2-carboxylic acid methyl ester was used in lieu of2-methylpropionaldehyde. Hydrolysis of the methyl ester using standardconditions afforded COMPOUND 271. ¹H NMR (CD₃OD) δ 1.05-4.05 (m, 28H,containing CH₃OH signal), 4.20-4.80 (m, 2H), 6.70-7.40 (m, 7H),7.93-8.20 (m, 1H); ES-MS m/z 625 (M+1).

Example 272

Compound 2726-[(R)-3-(1-{3-[(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-2-oxo-4-phenyl-imidazolidin-1-ylmethyl]-nicotinicacid

6-Formyl-nicotinic acid methyl ester was used in lieu of2-propionaldehyde. Hydrolysis of the methyl ester using standardconditions afforded COMPOUND 272. ¹H NMR (CD₃OD) δ 1.10-1.40 (m, 4H),1.60-2.10 (m, 5H), 2.32 (s, 3H), 2.45 (s, 3H), 2.80-3.90 (m, 12H, CH₃OHsignal), 4.61 (s, 2H), 4.75-4.85 (m, 1H, CH₃OH signal), 7.15-7.55 (m,7H), 8.20-8.40 (m, 1H), 9.10 (s, 1H); ES-MS m/z 620 (M+1).

Examples 273 and 274 were prepared following similar chemistry exceptthe first step involved N-alkylation of((R)-2-amino-1-phenyl-ethyl)-carbamic acid tert-butyl ester with acommercially available bromide.

Example 273

Compound 2736-Chloro-2,4-dimethyl-N-{3-[4-((R)-5-phenyl-3-pyrimidin-2-yl-2-thioxo-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-nicotinamide

COMPOUND 273 was isolated as a yellow foam (1:1 mixture ofdiastereomers). ¹H NMR (CDCl₃) δ 0.69-0.97 (m, 10H), 1.35-1.80 (m, 6H),2.04 (m, 3H), 2.24 (m, 1H), 2.34 (s, 3H), 2.35 (s, 3H), 2.42-2.81 (m,14H), 3.17 (m, 1H), 3.36 (m, 1H), 3.66 (m, 1H), 3.96 (m, 3H), 4.19 (m,1H), 4.32 (m, 1H), 4.54 (m, 2H), 4.73 (m, 2H), 7.00 (m, 2H), 7.15 (m,2H), 7.31 (m, 10H), 8.54 (d, 1H, J=6.6 Hz), 8.66 (m, 5H); ¹³C NMR(CDCl₃) δ 13.22, 13.74, 18.81, 22.21, 29.00, 29.90, 30.00, 30.50, 31.08,31.43, 39.97, 40.22, 42.95, 43.50, 51.45, 51.68, 54.42, 54.51, 56.81,57.24, 57.32, 60.07, 60.76, 116.50, 122.56, 125.56, 128.33, 129.13,133.08, 141.57, 147.83, 148.03, 150.22, 155.50, 155.59, 157.66, 158.43,166.67, 167.27, 178.71; ES-MS m/z 600 (M+Na). Anal. Calcd. forC₃₀H₃₆N₇ClSO·0.2CH₂Cl₂·0.6CH₄O: C, 60.21; H, 6.37; N, 15.96; Cl, 8.08;S, 5.22. Found: C, 60.09; H, 6.23; N, 15.74; Cl, 8.26; S, 5.19.

Example 274

Compound 2742-[(R)-3-(1-{3-[(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-2-oxo-4-phenyl-imidazolidin-1-yl]-propionicacid

Hydrolysis of the methyl ester using standard conditions affordedCOMPOUND 274. ¹H NMR (CDCl₃) mixture of diastereoisomers δ 1.20-4.95 (m,30H), 6.77-8.35 (m, 7H); ¹³C NMR (CDCl₃) δ 11.83, 12.34, 12.62, 12.75,14.89, 15.26, 19.10, 22.32, 26.32, 27.26, 31.06, 31.44, 36.45, 45.20,49.58, 49.81, 50.03, 50.89, 51.72, 51.85, 54.63, 55.28, 57.82, 58.81,122.51, 122.58, 126.35, 127.46, 127.65, 128.09, 128.25, 128.72, 129.07,132.04, 141.22, 147.61, 147.74, 149.86, 155.33, 160.72, 161.16, 168.37,168.49, 175.90, 128.77, 132.66, 132.80, 143.44, 143.64, 147.59, 147.73,150.12, 155.37, 159.93, 166.93, 167.53; ES-MS m/z 557 (M+1).

Example 275

Compound 2756-Chloro-2,4-dimethyl-N-(3-{4-[(R)-3-(1-methylcarbamoyl-ethyl)-2-oxo-5-phenyl-imidazolidin-1-yl]piperidin-1-yl}-butyl)-nicotinamide

Following general procedure E,2-[(R)-3-(1-{3-[(6-chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-2-oxo-4-phenyl-imidazolidin-1-yl]-propionicacid (COMPOUND 274) and methylamine hydrochloride afforded the COMPOUND275. ¹H NMR (CDCl₃) mixture of diastereoisomers δ 1.00-4.50 (m, 33H),6.60 (s, 0.5H), 6.46 (s, 0.5H), 7.03 (s, 1H), 7.16-7.33 (m, 5H),7.67-8.15 (m, 1H); ¹³C NMR (CDCl₃) δ 12.95, 13.10, 13.62, 13.77, 18.88,22.16, 26.10, 26.18, 28.88, 31.16, 31.63, 38.56, 44.31, 49.08, 49.16,49.40, 51.17, 51.34, 55.85, 59.39, 59.72, 59.90, 122.62, 124.12, 124.85,126.20, 126.28, 126.38, 128.41, 129.01, 141.87, 147.47, 160.25, 171.70;ES-MS m/z 570 (M+1).

Example 276

Compound 2766-Chloro-2,4-dimethyl-N-{3-[4-((R)-5-phenyl-3-pyridin-2-yl-2-thioxo-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-nicotinamide

To a solution of (R)-(−)-2-phenylglycine (3.83 g, 25.3 mmol) in 1M NaOH(35 ml) was added a solution of Boc₂O (6.14 g, 28.1 mmol) in t-BuOH (20ml). The resulting suspension was stirred at room temperature for 1hour. The volatile solvent was removed under reduced pressure and theremaining solution was adjusted to pH 3 with 4M HCl. The resultingsuspension was diluted with CHCl₃ (50 ml), the layers were separated andthe aqueous solution was extracted with CHCl₃ (25 ml×2). The combinedorganic solution was dried (Na₂SO₄), filtered and concentrated underreduced pressure, to give crude(R)-tert-butoxycarbonylamino-phenyl-acetic acid as a colorless oil (6.92g, quantitative).

To a solution of (R)-tert-butoxycarbonylamino-phenyl-acetic acid (510mg, 2.03 mmol) in THF (10 ml) at 0° C. was added NMM (205 mg, 2.03 mmol)in THF (1 ml) and the mixture was stirred at 0° C. for minutes. Isobutylchloroformate (0.26 ml, 2.0 mmol) was added, the mixture stirred for anadditional 5 minutes at 0° C. then 2-aminopyridine (382 mg, 4.06 mmol)in THF (2 ml) was added dropwise over 10 minutes. The resulting solutionwas stirred at room temperature for 5.5 hours. Standard work-up andpurification gave the crude amide (450 mg). Using general procedure C,the carbamate gave the amine, which was subsequently reduced withBH₃-THF (1.0M in THF, 4.1 ml, 4.1 mmol) in THF (10 ml) at reflux andtreated with MeOH (10 ml) then 6N HCl (11 ml) at reflux to afford(R)-1-phenyl-N²-pyridin-2-yl-ethane-1,2-diamine (109 mg, 25% over 3steps) after basic work up and purification.

Using general procedure A, the above amine (109 mg, 0.511 mmol) and[3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester (180 mg,0.666 mmol) afforded(3-{4-[(R)-1-phenyl-2-(pyridin-2-ylamino)-ethylamino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (182 mg, 76%).

To the above substrate (182 mg, 0.389 mmol) and Et₃N (0.11 ml, 0.79mmol) in CH₂Cl₂ (7.8 ml) cooled to 0° C. was added thiophosgene (0.033ml, 0.43 mmol) in CH₂Cl₂ (1 ml) dropwise and the mixture was stirred at0° C. for 10 minutes and at room temperature for 1 hour. Standardwork-up and purification gave3,3-dimethyl-N-{3-[4-((R)-5-phenyl-3-pyridin-2-yl-2-thioxo-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-butyramide(84 mg, 42%) as a yellow oil.

Using general procedure C with the above carbamate (84 mg, 0.16 mmol)then general procedure E with the resulting amine and6-chloro-2,4-dimethylnicotinic acid hydrochloride (23 mg, 0.10 mmol)gave COMPOUND 276 as a yellow foam (17 mg, 44%). ¹H NMR (CDCl₃) δ0.71-1.06 (m, 10H), 1.25-1.79 (m, 6H), 1.92-2.07 (m, 3H), 2.22 (td, 1H,J=11.7, 1.8 Hz), 2.31-2.82 (m, 20H), 3.14-3.22 (m, 1H), 3.33-3.40 (m,1H), 3.64-3.72 (m, 1H), 3.89-4.02 (m, 3H), 4.19-4.23 (m, 1H), 4.32-4.35(m, 1H), 4.55-4.70 (m, 4H), 6.98-7.02 (m, 2H), 7.15 (s, 1H), 7.16 (s,1H), 7.22-7.36 (m, 10H), 7.64-7.70 (m, 2H), 8.29-8.30 (m, 2H), 8.46 (brd, 1H, J=7.5 Hz), 8.60 (br s, 1H), 8.73 (s, 1H), 8.76 (s, 1H); ¹³C NMR(CDCl₃) δ 13.21, 13.70, 18.80, 22.19, 29.27, 29.70, 30.02, 30.25, 30.58,31.11, 31.52, 39.92, 40.15, 43.05, 43.62, 51.49, 51.76, 54.59, 56.49,57.07, 57.18, 60.01, 60.65, 117.59, 119.50, 122.58, 125.56, 128.25,129.10, 132.98, 136.42, 142.05, 147.45, 147.75, 147.93, 150.28, 152.70,155.45, 155.54, 166.76, 167.31, 179.15; ES-MS m/z 577 (M+H).

Examples 277 to 280 were prepared using similar chemistry.

Example 277

Compound 2776-Chloro-N-{3-[4-((R)-3-cyclopropyl-2-oxo-5-phenyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

Cyclopropylamine and triphosgene were used in lieu of 2-aminopyridineand thiophosgene, respectively. ¹H NMR (CDCl₃) δ 0.39-2.77 (m, 25H),2.82-3.05 (m, 1H), 3.09-4.18 (m, 5H), 7.11 (s, 1H), 7.20-7.39 (m, 5H),8.13-8.29 (br d, 1H); ¹³C NMR (CDCl₃) δ 5.54, 5.78, 13.41, 13.89, 19.23,22.53, 26.37, 29.58, 30.60, 30.90, 31.97, 40.00, 43.56, 44.28, 51.89,52.07, 52.47, 54.34, 55.28, 55.56, 60.09, 60.78, 123.00, 126.47, 128.29,129.15, 143.44, 143.65, 148.01, 148.14, 150.49, 155.79, 161.59, 167.25.Anal. Calcd. for C₂₉H₃₈N₅ClO₂·0.2CH₂Cl₂: C, 64.82; H, 7.15; N, 12.94.Found: C, 64.51; H, 7.14; N, 12.62; ES-MS m/z 524 (M+H).

Example 278

Compound 2786-Chloro-N-{3-[4-((R)-3-cyclopropyl-2-thioxo-5-phenyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

Cyclopropylamine was used in lieu of 2-aminopyridine. ¹H NMR (CDCl₃) δ0.41-3.0 (m, 25H), 3.04-4.55 (m, 6H), 7.00-7.36 (m, 6H), 8.36-8.79 (brd, 1H); ¹³C NMR (CDCl₃) δ 6.05, 7.73, 13.46, 14.05, 19.20, 22.55, 29.72,30.09, 31.63, 32.20, 40.33, 43.31, 44.01, 51.90, 52.24, 54.75, 57.73,58.18, 58.32, 60.42, 61.22, 122.95, 125.92, 128.60, 129.43, 142.92,150.46, 184.11; Anal. Calcd. for C₂₉H₃₈N₅ClOS·0.4·CH₂Cl₂·0.2C₆H₁₄: C,62.15; H, 7.09; N, 11.84. Found: C, 62.23; H, 7.18; N, 11.84; ES-MS m/z540 (M+H).

Example 279

Compound 2796-Fluoro-N-{3-[4-((R)-3-tert-butyl-2-oxo-5-phenyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

tert-Butyl amine and triphosgene were used in lieu of 2-aminopyridineand thiophosgene, respectively. ¹H NMR (CDCl₃) δ 0.73-1.00 (m, 4H), 1.27(s, 9H), 1.41-2.16 (m, 7H), 2.32 (double s, 3H), 2.50 (double s, 3H),2.55-4.20 (m, 9H), 6.68 (s, 1H), 7.14-7.41 (m, 5H), 7.77-8.18 (doublebroad, 1H); ¹³C NMR (CDCl₃) δ 12.99, 13.51, 19.20, 21.95, 27.42, 28.90,29.92, 30.54, 30.78, 31.50, 31.83, 39.49, 43.41, 44.19, 50.77, 51.77,52.17, 53.09, 53.44, 54.66, 54.84, 59.41, 60.13, 107.19, 107.67, 126.31,127.90, 128.70, 131.88, 143.20, 143.33, 150.52, 153.61, 153.81, 160.78,163.98, 167.19, 167.71; ES-MS m/z 524 (M+H).

Example 280

Compound 280 5,7-Dimethyl-imidazo[1,2-a]pyridine-6-carboxylic acid{3-[4-((R)-3-tert-butyl-2-oxo-5-phenyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-amide

5-Bromo-4,6-dimethyl-pyridin-2-ylamine (1.51 g, 7.5 mmol) andchloroacetaldehyde (0.95 ml, 50% in water, 7.5 mmol) were mixed withtoluene (12 ml). The mixture was heated to reflux for 3 h, upon whichtime a dark solid residue appeared at the bottom of the reaction flask.After cooling down to rt, NaHCO₃ (20 ml, sat. aq.) and CH₂Cl₂ (20 ml)were added. Layers were separated and the aqueous layer was furtherextracted with CH₂Cl₂ (20 ml×2). The combined CH₂Cl₂ was dried (Na₂SO₄),filtered and concentrated. The residue was purified by columnchromatography on silica gel (CH₂Cl₂/CH₃OH, 18:1) to give the6-bromo-5,7-dimethyl-imidazo[1,2-a]pyridine as a yellow oil (985 mg,58%, contaminated with some starting material).

6-Bromo-5,7-dimethyl-imidazo[1,2-a]pyridine (985 mg, 4.26 mmol) wasdissolved in DMF (15 ml). To this solution was added Zn(CN)₂ (512 mg,4.36 mmol), Pd₂(dba)₃ (40 mg, 0.044 mmol) and DPPF (49 mg, 0.088 mmol).The mixture was heated at 120° C. for 48 h. The mixture was thenconcentrated under vacuum and the residue was taken into CH₂Cl₂ (40 ml)and washed with H₂O (30 ml×2) and brine (20 ml). The organic layer wasconcentrated and the residue was purified by column chromatography onsilica gel (CH₂Cl₂/CH₃OH, 18:1) to give5,7-dimethyl-imidazo[1,2-a]pyridine-6-carbonitrile (747 mg, 99%).

The above-prepared nitrile (500 mg, 2.9 mmol) was dissolved in a mixtureof H₂SO₄ (conc. 4 ml) and H₂O (1 ml). The mixture was heated at 120° C.for 16 h. It was then cooled to 90° C. and NaNO₂ (1.4 g, 20 mmol) wasadded in small portions over 10 min. The reaction was heated at 90° C.for and additional 1 h and then cooled to rt and poured into anice-water mixture (˜20 ml). The chilled mixture was basified to PH=12using 10N NaOH. The aqueous mixture was then washed with CH₂Cl₂ (15ml×2) to remove impurities. It was then acidified to PH=2. After beingconcentrated under high vacuum to dryness, the residue was extractedwith CH₂Cl₂/CH₃OH (4/1, 30 ml×3). The combined extracts wereconcentrated to give 5,7-dimethyl-imidazo[1,2-a]pyridine-6-carboxylicacid (500 mg, 90% containing impurities) as a beige solid. ¹H NMR(CDCl₃) δ 2.56 (s, 3H), 2.83 (s, 3H), 7.74 (s, 1H), 8.08 (d, 1H, J=1.8Hz), 8.22 (d, 1H, J=1.8 Hz).

¹H NMR (CDCl₃) rotameric mixtures δ 0.75-4.00 (m, 35H), 6.97-7.05 (m,2H), 7.22-7.47 (m, 5H), 7.66 (s, 1H), 7.96-7.99 (m, 1H); ES-MS m/z 545(M+H).

Example 281

Compound 2816-Cyano-2,4-dimethyl-N-{3-[4-(2-oxo-5-{2,5-difluorophenyl}-3-cyclohexyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-nicotinamide

Sodium cyanide (1.38 g, 28.2 mmol) and ammonium chloride (0.75 g, 14.1mmol) were dissolved in ammonium hydroxide (14 ml). A methanol (7 mL)solution of 2,5-difluorobenzaldehyde (2.00 g, 14.1 mmol) was added tothe stirring ammonium hydroxide solution. The reaction was left to stirat room temperature for three hours. After the reaction was complete,the solvent mixture was removed in vacuo, and the solid residuedissolved in 6M HCl (14 ml). This acid solution was refluxed for twohours. Again, after the reaction was complete, the volatiles wereremoved under vacuum. The solid residue was dissolved in dioxane (14ml). Boc₂O (3.07 g, 14.1 mmol) and NaOH (2.8 ml of 10M solution, 28 mlof 1M solution) were added in succession. The reaction was allowed tostir at room temperature overnight. The basic solution was diluted withH₂O (˜100 ml) such that the pH reached ˜9. Impurities were removed byextracting this basic aqueous phase with DCM (3×100 ml). The basicsolution was then acidified to pH ˜3 with dilute aqueous HCl. Theproduct was extracted from this aqueous phase with DCM (3×100 ml), anddried over Na₂SO₄. The solvent was removed by rotary evaporation toyield tert-butoxycarbonylamino-(2,5-difluorophenyl)-acetic acid (1.84 g,46%).

Using general procedure E,tert-butoxycarbonylamino-(2,5-difluorophenyl)-acetic acid (1.84 g, 6.40mmol) and cyclohexylamine (730 μL, 634 mg, 6.40 mmol) afforded[cyclohexylcarbamoyl-(2,5-difluorophenyl)-methyl]-carbamic acidtert-butyl ester (2.12 g, 90%).

Using general procedure C, the above carbamate (2.12 g, 5.74 mmol) gavethe crude amine, which was subsequently reduced with BH₃-THF (1.0M inTHF, 17.2 ml, 17.2 mmol) in THF (20 ml) at reflux for 3 hours. After thereaction was complete, it was treated with MeOH (22 ml) and refluxed for15 minutes. Removal of all volatiles gave a crude solid, which was thendissolved in ethylenediamine (22 ml) and heated to 60° C. for 20minutes. The reaction was quenched with a saturated solution of NaHCO₃,and the product extracted with DCM (3×100 ml). The organic solution wasdried over Na₂SO₄ and the solvent removed to afford crudeN²-cyclohexyl-1-(2,5-difluorophenyl)-ethane-1,2-diamine which waspurified by column chromatography (750 mg, 52%).

Using general procedure A,N²-cyclohexyl-1-(2,5-difluorophenyl)-ethane-1,2-diamine (750 mg, 2.95mmol) and [3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butylester (797 mg, 2.95 mmol) afforded{3-[4-(2-cyclohexylamino-1-{2,5-difluorophenyl}-ethylamino)-piperidin-1-yl]-butyl}-carbamicacid tert-butyl ester (1.34 g, 89%).

The diamine product (499 mg, 0.983 mmol) was then dissolved in 4 ml ofDCM. Pyridine (160 μL, 156 mg, 2.37 mmol) was added and the mixture wascooled to 0° C. Triphosgene (117 mg, 0.393 mmol) was added slowly to thestirring solution. The reaction was allowed to warm up to roomtemperature with stirring for two hours. The reaction was then quenchedby the addition of 50 ml of a saturated solution of NaHCO₃. Standardworkup and purification by flash chromatography gave{3-[4-(3-cyclohexyl-5-{2,5-difluorophenyl}-2-oxo-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-carbamicacid tert-butyl ester (470 mg, 90%).

Using general procedure C with the above carbamate, and subsequentlygeneral procedure E with the resulting amine (56 mg, 0.130 mmol) and6-cyano-2,4-dimethylnicotinic acid (27 mg, 0.156 mmol) afforded COMPOUND281 as an off-white foam (53 mg, 69%). ¹H NMR (CDCl₃) δ 0.93-1.00 (m,3H), 1.04-1.26 (m, 3H), 1.36-1.48 (m, 4H), 1.51-1.78 (m, 10H), 1.87-2.11(m, 1H), 2.38-2.46 (m, 4H), 2.58 (d, 3H, J=3.3 Hz), 2.61-2.74 (m, 3H),2.99 (m, 1H), 3.23-3.38 (m, 2H), 3.68-3.72 (m, 3H), 3.91 (m, 1H),4.45-4.56 (m, 1H), 7.02 (m, 2H), 7.45 (s, 1H), 8.02-8.11 (m, 1H); ¹³CNMR (CDCl₃) δ 13.15, 13.50, 18.80, 22.23, 25.42, 25.51, 29.45, 29.68,30.12, 30.40, 30.64, 31.05, 31.70, 39.43, 39.51, 43.51, 44.04, 47.17,47.25, 51.27, 51.62, 51.84, 52.08, 52.34, 59.34, 59.88, 113.91, 114.23,115.77, 115.88, 116.09, 116.20, 116.63, 117.07, 117.21, 127.73, 132.51,136.56, 136.63, 145.44, 145.49, 156.56, 156.62, 157.37, 159.52, 160.60,166.40, 166.75; ES-MS m/z 593 (M+H), 615 (M+Na). Anal. Calcd. forC₃₃H₄₂N₆O₂F₂ 0.1 (CH₂Cl₂): C, 66.13; H, 7.07; N, 13.98. Found: C, 65.73;H, 7.16; N, 13.94.

Examples 282 to 291 were prepared following similar chemistry.

Example 282

Compound 2826-Chloro-N-(3-{4-[(R)-3-(1,1-dimethyl-propyl)-2-oxo-5-phenyl-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

tert-Amylamine was used in lieu of cyclohexylamine. Mixture ofdiastereoisomers: ¹H NMR (CDCl₃) δ 0.63-1.00 (m, 8H), 1.21-1.38 (m, 7H),1.41-2.14 (m, 8H), 2.24-2.81 (m, 9H), 2.97-3.44 (m, 2H), 3.47-3.76 (m,2H), 3.86-4.11 (m, 1H), 7.12 (s, 1H), 7.19-7.40 (m, 5H), 8.08 and 8.32(br s, 1H); ¹³C NMR (CDCl₃) δ 9.1, 13.3, 14.0, 19.2, 22.5, 25.6, 28.2,29.2, 30.4, 30.7, 31.3, 32.1, 32.2, 32.9, 40.0, 40.4, 43.6, 44.5, 51.6,52.1, 52.7, 54.8, 54.9, 56.2, 60.1, 60.9, 123.0, 126.6, 127.0, 128.2,129.1, 144.1, 148.0, 155.8, 161.0; ES-MS m/z 554 (M+H). Anal. Calcd. forC₃₁H₄₄ClN₅O₂: C, 67.19; H, 8.00; N, 12.64. Found: C, 67.15; H, 8.10; N,12.45.

Example 283

Compound 2836-Chloro-2,4-dimethyl-N-(3-{4-[(R)-2-oxo-5-phenyl-3-(2,2,2-trifluoro-ethyl)-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-nicotinamide

2,2,2-Trifluoroethylamine was used in lieu of cyclohexylamine. Mixtureof diastereoisomers: ¹H NMR (CDCl₃) δ 0.75-1.15 (m, 4H), 1.21-1.75 (m,7H), 1.82-2.12 (m, 1H), 2.33 and 2.34 (s, 3H), 2.52 and 2.54 (s, 3H),2.57-2.79 (m, 2H), 3.07-3.57 (m, 3H), 3.58-3.99 (m, 4H), 4.07-4.30 (m,1H), 7.11 and 7.12 (s, 1H), 7.18-7.41 (m, 5H), 8.08 and 8.21 (br s, 1H);¹³C NMR (CDCl₃) δ 13.4, 13.9, 19.2, 22.5, 29.7, 30.5, 31.0, 31.7, 32.0,40.1, 40.2, 43.6, 44.2, 46.0, 46.4, 52.1, 52.4, 52.6, 54.0, 55.6, 57.0,60.2, 60.8, 123.0, 123.1, 126.5, 126.6, 128.7, 128.8, 129.4, 142.8,148.1, 155.7; ES-MS m/z 566 (M+H). Anal. Calcd. forC₂₈H₃₅ClF₃N₅O₂·0.31H₂O: C, 59.41; H, 6.23; N, 12.37. Found: C, 58.88; H,6.39; N, 12.04.

Example 284

Compound 284N-(3-{4-[3-tert-Butyl-5-(3-chloro-phenyl)-2-oxo-imidazolidin-1-1]-piperidin-1-yl}-butyl)-6-fluoro-2,4-dimethyl-nicotinamide

To a 0° C. mixture of NH₄Cl (1.34 g, 25.1 mmol) and NaCN (1.35 g, 27.5mmol) in NH₄OH—H₂O (15.6 ml) was added 3-chloro-benzaldehyde (2.85 ml,25 mmol) in MeOH (25 ml) dropwise and then the resulting mixture wasstirred at room temperature for 4 hours. The solvent was partiallyremoved and a standard aqueous work-up gave a yellow solid, which wassubsequently treated with 6N HCl (40 ml) and heated at 115° C.overnight. The mixture was concentrated in vacuo and diluted withaqueous NaOH (2.0 g in 30 ml) to adjust pH˜14. 1,4-Dioxane (30 ml) andBoc₂O (9.82 g, 45 mmol) was added and the mixture stirred at roomtemperature overnight. The mixture was concentrated and acidified withsaturated aqueous KHSO₄ to pH˜4. The aqueous was extracted with CH₂Cl₂,dried (Na₂SO₄) and concentrated under reduced pressure to givetert-butoxycarbonylamino-(3-chloro-phenyl)-acetic acid (4.73 g, 66% over3 steps).

tert-Butylamine was used in lieu of cyclohexylamine. ¹H NMR (CDCl₃)mixture of diastereoisomers: δ 0.66-0.98 (m, 1H), 1.05-1.41 (m, 1H),1.43-1.76 (m, 5H), 1.84 and 2.11 (m, 1H), 2.36 and 2.38 (s, 3H), 2.49and 2.51 (s, 3H), 2.22-2.81 (m, 4H), 2.93-3.71 (m, 5H), 3.86-4.09 (m,2H), 6.69 (s, 1H), 7.10-7.19 (m, 1H), 7.21-7.35 (m, 3H), 7.96 and 8.12(br s, 1H); ¹³C NMR (CDCl₃) δ 13.4, 14.0, 19.6, 22.3, 27.8, 29.2, 30.4,31.0, 31.2, 32.2, 40.0, 40.2, 43.6, 44.5, 50.9, 52.0, 52.2, 52.5, 54.3,54.4, 59.9, 60.7, 107.6, 108.1, 124.7, 124.8, 126.7, 128.5, 130.5,135.0, 146.0, 146.2, 150.9, 160.9; ES-MS m/z 558 (M+1). Anal. Calcd. forC₃₀H₄₁ClFN₅O₂·0.24H₂O: C, 64.05; H, 7.43; N, 12.45. Found: C, 64.07; H,7.38; N, 12.35.

Example 285

Compound 2856-Chloro-N-(3-{4-[5-(3-chloro-phenyl)-3-isopropyl-2-thioxo-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

Isopropylamine and thiophosgene was used in lieu of cyclohexylamine andtriphosgene, respectively. 1:1 Ratio of diastereomers. ¹H NMR (CDCl₃) δ0.59-0.65 (m, 1H), 0.90-0.94 (m, 3H), 1.04-1.12 (m, 3H), 1.14-1.15 (m,3H), 1.24-1.29 (m, 1H), 1.42-1.51 (m, 1H), 1.63-1.71 (m, 1H), 1.75-1.85(m, 1H), 1.88-2.16 (m, 1H), 2.33-2.49 (m, 4H), 2.56-2.75 (m, 7H),3.07-3.37 (m, 2H), 3.60-4.14 (m, 3H), 4.44-4.57 (m, 1H), 4.89-5.29 (m,1H), 7.02-7.06 (m, 1H), 7.13 (s, 1H), 7.18 (d, 1H, J=6.9 Hz), 7.29 (s,2H), 8.82 and 8.50 (s and d, 1H, J=6.6 Hz); ¹³C NMR (CDCl₃) δ 13.15,13.74, 18.57, 18.64, 18.81, 19.79, 19.85, 22.14, 29.17, 29.62, 30.35,31.22, 32.27, 39.96, 40.40, 42.90, 43.54, 46.95, 47.02, 50.99, 51.05,51.48, 51.91, 53.45, 54.31, 56.87, 60.17, 60.92, 122.62, 123.65, 125.69,128.38, 130.45, 133.08, 133.17, 134.89, 145.28, 145.35, 148.02, 148.16,149.97, 155.50, 155.58, 166.51, 157.23, 180.79; ES-MS m/z 578 (M+H).

Example 286

Compound 2866-Chloro-N-{3-[4-(3-cyclohexyl-2-oxo-5-thiophen-3-yl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

To a solution of NH₄Cl (1.07 g, 20.0 mmol) and NaCN (0.980 g, 20.0 mmol)in ammonium hydroxide was added a solution of thiophene-3-carbaldehyde(1.12 g, 10.0 mmol) in methanol (5 ml). The mixture was stirred at roomtemperature for 4 h. 6 N HCl (10 ml) was added to the flask and themixture was heated at refluxing temperature for 2 h. Solvents wereevaporated under reduced pressure. The dried pale yellow solid wasdissolved in methanol (10 ml) and 1N NaOH (20 ml). Boc₂O (2.06 g) wasadded to the reaction and the mixture was stirred at room temperaturefor 2 h. The mixture was acidified with 1 N HCl to pH=4-5, extractedwith CHCl₃ (4×30 ml). The combined organic extracts were dried (MgSO₄)and concentrated to give a brown oil. This was purified by columnchromatography on silica gel, eluted with CH₂Cl₂/MeOH (90:10) to givetert-butoxycarbonylamino-thiophen-3-yl-acetic acid (1.34 g, 52%).

¹H NMR (CDCl₃) δ 0.91-1.04 (m, 4H), 1.20-1.37 (m, 5H), 1.50-1.75 (m,8H), 1.85-2.13 (m, 1H), 2.32, and 2.33 (double s, 3H), 2.51, and 2.53(double s, 3H), 2.64-2.74 (m, 2H), 2.97-3.03 (m, 1H), 3.10-3.40 (m, 1H),3.56 (t, 2H, J=6.0 Hz), 3.61-4.30 (m, 2H), 6.99-7.01 (m, 1H), 7.07-7.10(m, 2H), 7.24-7.27 (m, 1H), 8.19-8.37 (m, 1H); ¹³C NMR (CDCl₃) δ 14.44,14.92, 20.22, 20.25, 23.53, 26.86, 26.92, 26.96, 30.29, 31.55, 31.87,32.72, 32.93, 41.02, 44.67, 45.45, 49.03, 49.08, 52.19, 52.39, 52.63,52.83, 53.13, 53.60, 61.16, 61.86, 122.70, 122.84, 127.06, 128.06,134.12, 134.26, 145.90, 146.08, 149.07, 149.23, 151.40, 151.46, 156.76,160.87, 168.23, 168.83; ES-MS m/z 572 (M+H). Anal Calcd. forC₃₀H₄₂N₅ClO₂S·0.6CH₂Cl₂: C, 58.98; H, 6.99; N, 11.24; Br, 37.11. Found:C, 59.12; H, 6.94; N, 11.17.

Example 287

Compound 2876-Chloro-2,4-dimethyl-N-{3-[4-(2-oxo-5-{2,5-difluoro-phenyl}-3-cyclohexyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-nicotinamide

COMPOUND 287 was isolated as an off-white foam. ¹H NMR (CDCl₃) δ0.94-1.05 (m, 6H), 1.19-1.43 (m, 7H), 1.56-1.78 (m, 14H), 1.99-2.15 (m,1H), 2.32 (m, 3H), 2.53 (m, 3H), 2.68-2.76 (m, 2H), 2.99 (m, 1H), 3.19(m, 1H), 3.47-3.57 (m, 1H), 3.71 (m, 2H), 3.91 (m, 1H), 4.43-4.54 (m,1H), 6.91-7.08 (m, 3H), 7.76-7.86 (m, 1H); ¹³C NMR (CDCl₃) δ 13.03,13.48, 18.83, 22.08, 25.50, 29.08, 30.05, 30.32, 31.09, 32.04, 39.23,43.36, 44.11, 47.39, 47.70, 51.30, 51.51, 51.88, 59.17, 59.98, 113.97,114.33, 115.71, 116.15, 116.62, 122.62, 132.58, 147.45, 150.05, 155.33,159.53, 167.18, 167.69; ES-MS m/z 602 (M+H), 624 (M+Na). Anal. Calcd.for C₃₂H₄₂N₅O₂F₂Cl 0.1CH₂Cl₂: C, 63.14; H, 6.97; N, 11.47. Found: C,62.75; H, 7.05; N, 11.24.

Example 288

Compound 2886-Fluoro-2,4-dimethyl-N-{3-[4-(2-oxo-5-{2,5-difluorophenyl}-3-cyclohexyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-nicotinamide

COMPOUND 288 was isolated as an off-white foam. ¹H NMR (CDCl₃) δ0.92-1.09 (m, 7H), 1.17-1.39 (m, 7H), 1.51-1.81 (m, 10H), 1.98-2.10 (m,1H), 2.36 (d, 3H, J=3.6 Hz), 2.40-2.49 (m, 1H), 2.48 (d, 3H, J=4.8 Hz),2.50-2.54 (m, 1H), 2.66-2.76 (m, 3H), 2.97 (m, 1H), 3.19 (m, 1H),3.38-3.55 (m, 2H), 3.62-3.74 (m, 3H), 3.86 (m, 1H), 4.45-4.63 (m, 1H),6.64 (s, 1H), 6.93-7.05 (m, 3H), 7.70-7.75 (m, 1H); ¹³C NMR (CDCl₃) δ13.10, 13.53, 19.15, 21.86, 25.50, 29.25, 29.94, 30.01, 30.33, 31.11,31.26, 32.06, 39.38, 43.36, 44.09, 47.29, 47.64, 48.22, 51.29, 51.49,51.74, 51.85, 52.08, 59.18, 59.92, 107.16, 107.71, 113.92, 114.26,115.77, 115.98, 116.09, 116.66, 116.92, 131.73, 150.29, 153.79, 157.36,159.58, 160.57, 160.82, 163.98, 167.35, 167.80; ES-MS m/z 586 (M+H), 608(M+Na). Anal. Calcd. for C₃₂H₄₂N₅O₂F₃ 0.1CH₂Cl₂: C, 64.89; H, 7.16; N,11.79. Found: C, 64.83; H, 7.11; N, 11.83.

Example 289

Compound 289N-(3-{4-[3-tert-Butyl-5-(3-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-6-chloro-2,4-dimethyl-nicotinamide

To a 0° C. mixture of NH₄Cl (535 mg, 10 mmol) and NaCN (539 mg, 11 mmol)in NH₄OH·H₂O (6.3 ml) was added 3-fluoro-benzaldehyde (1.06 ml, 10 mmol)in MeOH (10 ml) dropwise and then the resulting mixture was stirred atroom temperature for 4 hours. The solvent was partially removed and astandard aqueous work-up gave a yellow oil, which was subsequentlytreated with 6N HCl (16 ml) and heated at 115° C. overnight. The mixturewas concentrated in vacuo and diluted with aqueous NaOH (460 mg in 25ml) to adjust pH˜14. 1,4-Dioxane (25 ml) and Boc₂O (2.41 g, 11 mmol) wasadded and the mixture stirred at room temperature overnight. The mixturewas concentrated and acidified with saturated aqueous KHSO₄ to pH˜4. Theaqueous was extracted with CH₂Cl₂, dried (Na₂SO₄) and concentrated underreduced pressure to give crudetert-butoxycarbonylamino-(3-fluoro-phenyl)-acetic acid.

tert-Butylamine was used in lieu of cyclohexylamine. 1:1 Ratio ofdiastereomers. ¹H NMR (CDCl₃) δ 0.88-0.92 (m, 4H), 1.22-1.24 (m, 1H),1.31-1.35 (m, 1H), 1.63-2.03 (m, 3H), 2.04-2.10 (m, 1H), 2.3 and 2.32(two s, 3H), 2.38-2.42 (m, 1H), 2.50 and 2.52 (two s, 3H), 2.64-2.73 (m,2H), 2.96-3.01 (m, 1H), 3.11 and 3.38 (two m, 1H), 3.56-3.60 (m, 2H),3.89-3.91 (m, 1H), 4.02-4.11 (m, 1H), 6.93-7.06 (m, 3H), 7.10 (d, 1H,J=2.7 Hz), 7.28-7.33 (m, 1H), 8.2 and 8.01 (s, d, 1H, J=6 Hz); ¹³C NMR(CDCl₃) δ 13.36, 13.99, 19.18, 22.49, 27.81, 29.23, 30.35, 30.65, 31.23,32.06, 32.22, 40.01, 40.34, 43.59, 44.40, 51.06, 52.00, 52.07, 52.56,53.52, 54.21, 54.29, 60.05, 60.82, 113.35, 113.65, 115.06, 115.34,122.19, 123.00, 130.67, 130.77, 133.17, 146.78, 148.12, 148.25, 150.44,155.78, 160.90, 161.75, 165.02, 167.16, 167.79; ES-MS m/z 559 (M+H).Anal. Calcd. for C₃₀H₄₁N₅ClO₂F·0.54H₂O: C, 63.45; H, 7.47; N, 12.33.Found: C, 63.48; H, 7.46; N, 12.18.

Example 290

Compound 290N-(3-{4-[3-tert-Butyl-5-(3-fluoro-phenyl)-2-oxo-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-6-fluoro-2,4-dimethyl-nicotinamide

tert-Butylamine was used in lieu of cyclohexylamine. 1:1 Ratio ofdiastereomers. ¹H NMR (CDCl₃) δ 0.88-0.92 (m, 4H), 1.22-1.24 (m, 1H),1.31-1.35 (m, 1H), 1.63-2.03 (m, 3H), 2.04-2.10 (m, 1H), 2.3 and 2.32(two s, 3H), 2.38-2.42 (m, 1H), 2.50 and 2.52 (two s, 3H), 2.64-2.73 (m,2H), 2.96-3.01 (m, 1H), 3.16 and 3.38 (two m, 1H), 3.40-4.07 (m, 4H),6.66 (s, 1H), 6.93-7.02 (m, 3H), 7.25-7.33 (m, 1H), 7.95 and 8.01 (twos, 1H); ¹³C NMR (CDCl₃) δ 13.36, 13.99, 19.18, 22.49, 27.81, 29.23,30.35, 30.65, 31.23, 32.06, 32.22, 40.01, 40.34, 43.59, 44.40, 51.06,52.00, 52.07, 52.56, 53.52, 54.21, 54.29, 60.05, 60.82, 107.57, 108.06,113.39, 113.68, 115.10, 115.38, 122.23, 130.67, 130.78, 132.12, 146.55,151.02, 153.97, 154.17, 160.93, 161.17, 161.73, 164.33, 165.00, 168.04;ES-MS m/z 542 (M+H). Anal. Calcd. for C₃₀H₄₁N₅O₂F₂·1.0H₂O: C, 64.38; H,7.74; N, 12.51. Found: C, 64.38; H, 7.48; N, 12.44.

Example 291

Compound 2916-Cyano-N-(3-{4-[5-(2-fluoro-5-methyl-phenyl)-3-isopropyl-2-oxo-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide

To a 0° C. mixture of NH₄Cl (234 mg, 4.37 mmol) and NaCN (238 mg, 4.86mmol) in NH₄OH·H₂O (3.0 ml) was added 2-fluoro-5-methyl-benzaldehyde(610 mg, 4.42 mmol) in MeOH (4.5 ml) dropwise and then the resultingmixture was stirred at room temperature for 2 hours. The solvent waspartially removed and a standard aqueous work-up gave a yellow oil,which was subsequently treated with 6N HCl (15 ml) and heated at refluxovernight. The mixture was concentrated in vacuo and diluted with 10NNaOH to adjust pH 13. MeOH (5 ml) and Boc₂O (1.0 g, 4.6 mmol) was addedand the mixture stirred at room temperature for 4 hours. Standardwork-up gave tert-butoxycarbonylamino-(2-fluoro-5-methyl)-acetic acid(155 mg, 12% over 3 steps).

Isopropylamine was used in lieu of cyclohexylamine. COMPOUND 291 wasisolated as a beige foam. ¹H NMR (CDCl₃) δ 0.87-0.96 (m, 4H), 1.04-1.07(m, 6H), 1.12-1.14 (m, 1H), 1.25-1.75 (m, 5H), 1.85-2.10 (m, 1H), 2.28(s, 3H), 2.36-2.39 (m, 3H), 2.45-2.57 (m, 4H), 2.73-2.76 (m, 2H),2.97-2.99 (m, 1H), 3.20-3.50 (m, 2H), 3.62-3.66 (m, 1H), 3.70-3.75 and3.80-3.85 (m, 1H), 4.15-4.19 (m, 1H), 4.40-4.45 and 4.55-4.60 (m, 1H),6.87-6.95 (m, 1H), 7.02-7.12 (m, 2H), 7.44 (s, 1H), 8.00-8.05 and8.10-8.15 (m, 1H); ¹³C NMR (CDCl₃) δ 11.71, 17.49, 18.23, 19.48, 20.91,27.93, 28.93, 29.66, 30.34, 38.07, 42.19, 42.67, 44.98, 46.96, 50.60,58.21, 58.71, 113.77, 114.06, 115.93, 126.48, 127.70, 128.62, 131.23,132.89, 135.24, 144.10, 155.24, 158.39, 165.19, 165.55; ES-MS m/z 549(M+H). Anal. Calcd. for C₃₁H₄₁N₆O₂F·0.1C₆H₁₄·0.3CH₂Cl₂: C, 65.74; H,7.44; N, 14.42. Found: C, 65.44; H, 7.30; N, 14.29.

Example 292

Compound 2926-Fluoro-2,4-dimethyl-N-{3-[4-((R)-2-oxo-5-phenyl-3-(tetrahydro-pyran-4-ylmethyl)-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-nicotinamide

Methyl tetrahydro-2-H-pyran-4-carboxylate (400 μL, 3.00 mmol) wasdissolved in a 5:1 mixture of 10M NaOH and MeOH (4.0 ml: 0.8 ml). Themixture was heated to 60° C. for 3 hours. After the reaction wascomplete, all volatiles were removed under high vacuum to leave aresidual solid. The residue was dissolved in H₂O and subsequentlyacidified to pH˜1 using aqueous HCl. The acidic aqueous phase wasextracted with DCM and dried over Na₂SO₄. The solvent was removed togive tetrahydro-pyran-4-carboxylic acid (339 mg, 87%), which was used inthe next step without further purification.

Using general procedure E, ((R)-2-amino-1-phenyl-ethyl)-carbamic acidtert-butyl ester (616 mg, 2.61 mmol) and tetrahydro-pyran-4-carboxylicacid (339 mg, 2.61 mmol) afforded((R)-1-phenyl-2-[(tetrahydro-pyran-4-carbonyl)-amino]ethyl)-carbamicacid tert-butyl ester (908 mg, 99%).

Using general procedure C,((R)-1-phenyl-2-[(tetrahydro-pyran-4-carbonyl)-amino]-ethyl)-carbamicacid tert-butyl ester (908 mg, 2.61 mmol) afforded(R)-tetrahydro-pyran-4-carboxylic acid (2-amino-2-phenyl-ethyl)-amide(450 mg, 70%).

(R)-tetrahydro-pyran-4-carboxylic acid (2-amino-2-phenyl-ethyl)-amide(450 mg, 1.82 mmol) was dissolved in dry THF; and 5.45 ml of borane-THFcomplex (1M in THF, 5.45 mmol) was added. The solution was refluxed for3 hours. The reaction was then cooled to room temperature. Methanol (7ml) was added slowly through the condenser, and the reaction brought toreflux for a further 15 minutes. The reaction was again cooled to roomtemperature; and the volatiles were removed under high vacuum. Moremethanol was added and subsequently evaporated (3×15 ml). The resultingresidue was dissolved in ethylenediamine (7 ml) and the solution washeated to 60° C. for 20 minutes. The reaction was then quenched with theaddition of a saturated aqueous solution of NaHCO₃. This aqueous phasewas extracted with DCM; and the organic extracts dried over Na₂SO₄. Thesolvent was removed in vacuo to give the crude product. Purification byflash chromatography over silica gel afforded(R)-1-Phenyl-N²-(tetrahydro-pyran-4-ylmethyl)-ethane-1,2-diamine (304mg, 72%).

Using general procedure A,(R)-1-Phenyl-N²-(tetrahydro-pyran-4-ylmethyl)-ethane-1,2-diamine (300mg, 1.28 mmol) and [3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acidtert-butyl ester (346 mg, 1.28 mmol) afforded[3-(4-{(R)-1-phenyl-2-[tetrahydro-pyran-4-ylmethyl)-amino-ethylamine}-piperidin-1-yl)-butyl]-carbamicacid tert-butyl ester (626 mg, 99%).

The diamine product (500 mg, 1.03 mmol) was then dissolved in 4 ml ofDCM. Pyridine (175 μL, 164 mg, 2.05 mmol) was added and the mixture wascooled to 0° C. Triphosgene (121 mg, 0.410 mmol) was added slowly to thestirring solution. The reaction was allowed to warm up to roomtemperature with stirring for two hours. The reaction was then quenchedby the addition of 50 ml of a saturated solution of NaHCO₃. Standardworkup and purification by flash chromatography gave{3-[4-((R)-2-oxo-5-phenyl-3-{tetrahydro-pyran-4-ylmethyl}-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-carbamicacid tert-butyl ester (377 mg, 72%).

Using general procedure C with the above carbamate, and subsequentlygeneral procedure E with the resulting amine (68 mg, 0.165 mmol) and6-fluoro-2,4-dimethylnicotinic acid (38 mg, 0.198 mmol) gave COMPOUND292 as an off-white foam (68 mg, 73%). ¹H NMR (CDCl₃) δ 0.84-0.92 (m,4H), 1.25-1.39 (m, 4H), 1.51-1.55 (m, 3H), 1.63-1.74 (m, 6H), 1.92-2.09(m, 1H), 2.27-2.33 (m, 1H), 2.37 (d, 3H, J=4.2 Hz), 2.42-2.46 (m, 1H),2.50 (d, 3H, J=6.6 Hz), 2.62-2.72 (m, 3H), 2.94-3.05 (m, 2H), 3.12-3.18(m, 2H), 3.33-3.39 (m, 2H), 3.93-3.98 (m, 2H), 4.12-4.23 (m, 1H), 6.67(s, 1H), 7.21-7.36 (m, 5H), 7.98-8.13 (m, 1H); ¹³C NMR (CDCl₃) δ 12.04,12.48, 18.19, 20.92, 28.01, 28.97, 29.38, 29.62, 29.68, 29.87, 30.47,30.74, 32.92, 38.43, 38.51, 42.36, 43.09, 48.81, 50.50, 50.83, 50.92,52.76, 54.07, 54.41, 58.32, 59.00, 66.56, 106.16, 106.65, 125.07,125.14, 127.02, 127.83, 130.73, 130.89, 141.96, 142.19, 149.41, 149.57,149.68, 152.56, 152.76, 159.78, 159.93, 162.94, 166.17, 166.70; ES-MSm/z 566 (M+H), 588 (M+Na). Anal. Calcd. for C₃₂H₄₄N₅O₃F 0.1CH₂Cl₂: C,67.14; H, 7.76; N, 12.20. Found: C, 66.85; H, 7.70; N, 12.02.

Examples 293 and 294 were prepared following similar chemistry.

Example 293

Compound 2936-Chloro-2,4-dimethyl-N-(3-{4-[(R)-2-oxo-5-phenyl-3-(tetrahydro-furan-2-ylmethyl)-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-nicotinamide

Tetrahydro-2-furoic acid was used in lieu oftetrahydro-pyran-4-carboxylic acid. Mixture of diastereoisomers: ¹H NMR(CDCl₃) δ 0.86-1.18 (m, 5H), 1.22-2.16 (m, 9H), 2.31 and 2.32 (s, 3H),2.34-2.81 (m, 4H), 2.50 and 2.52 (s, 3H), 3.05-4.21 (m, 1H), 7.10 and7.11 (s, 1H), 7.14-7.38 (m, 5H), 7.80 and 8.21 (br s, 1H); ¹³C NMR(CDCl₃) δ 12.0, 12.5, 17.8, 21.1, 24.6, 24.7, 27.7, 28.0, 29.5, 30.6,38.6, 38.8, 42.9, 46.9, 47.0, 50.7, 50.9, 51.1, 53.1, 53.6, 54.6, 58.7,59.3, 67.0, 67.1, 121.6, 125.2, 125.6, 126.8, 127.7, 131.7, 131.8,142.2, 142.4, 146.5, 146.6, 149.1, 149.2, 154.3, 159.8, 159.9, 165.9,166.4; ES-MS m/z 568 (M+H). Anal. Calcd. for C₃₁H₄₂ClN₅O₃·0.43H₂O: C,65.53; H, 7.45; N, 12.33. Found: C, 64.73; H, 7.50; N, 11.79.

Example 294

Compound 2946-Chloro-2,4-dimethyl-N-(3-{4-[(R)-5-phenyl-3-(tetrahydro-furan-2-ylmethyl)-2-thioxo-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-nicotinamide

Tetrahydro-2-furoic acid and thiophosgene were used in lieu oftetrahydro-pyran-4-carboxylic acid and triphosgene, respectively.Mixture of diastereoisomers: ¹H NMR (CDCl₃) δ 0.88-0.56 (m, 1H),1.02-0.87 (m, 3H), 1.12 (m, 1H), 1.21-1.40 (m, 1H), 1.41-2.06 (m, 7H),2.11-2.80 (m, 7H), 2.32 and 2.34 (s, 3H), 3.06-3.42 (m, 2H), 3.43-3.54(m, 1H), 3.56-4.27 (m, 8H), 3.37-4.57 (m, 1H), 7.08-7.37 (m, 6H), 8.38and 8.56 (m, 1H); ¹³C NMR (CDCl₃) δ 14.1, 19.2, 22.5, 25.8, 26.1, 28.8,29.5, 30.3, 32.3, 40.3, 40.6, 43.4, 44.1, 51.1, 51.6, 52.0, 52.3, 55.5,58.0, 58.2, 58.3, 58.9, 60.3, 61.1, 68.3, 68.4, 123.0, 126.1, 126.2,128.5, 128.6, 129.3, 129.3, 129.4, 143.4, 167.4; ES-MS m/z 584 (M+H).Anal. Calcd. for C₃₁H₄₂ClN₅O₂S·0.3H₂O: C, 63.73; H, 7.25; N, 11.99; S,5.49. Found: C, 63.20; H, 7.25; N, 11.68; S, 5.18.

Example 295

Compound 2956-Chloro-2,4-dimethyl-N-(3-{4-[(R)-2-oxo-5-phenyl-3-(tetrahydro-pyran-4-yl)-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-nicotinamide

Following general procedure A: ((R)-2-amino-1-phenyl-ethyl)-carbamicacid tert-butyl ester (269 mg, 1.14 mmol), tetrahydro-4H-pyran-4-one(0.12 ml, 1.3 mmol) and NaBH(OAc)₃ (340 mg, 1.60 mmol) in CH₂Cl₂ (8.0ml) was stirred at room temperature for 18 hours. Standard work-up andpurification by flash column chromatography on silica (CH₂Cl₂/MeOH,19:1) gave [(R)-1-phenyl-2-(tetrahydro-pyran-4-ylamino)-ethyl]-carbamicacid tert-butyl ester as a colorless oil (333 mg, 91%). ¹H NMR (CDCl₃) δ0.80-1.36 (m, 3H), 1.41 (s, 9H), 1.68-1.82 (m, 2H), 2.61 (tt, 1H,J=10.3, 4.1 Hz), 2.93 (d, 2H, J=5.1 Hz), 3.35 (tdd, 2H, J=11.6, 5.6, 2.2Hz), 3.88-3.96 (m, 2H), 4.74 (br s, 1H), 5.45 (br d, 1H, J=5.7 Hz),7.22-7.35 (m, 5H).

A solution of the tert-butyl carbamate (333 mg, 1.04 mmol) and TFA (1.0ml) in CH₂Cl₂ (6.0 ml) was stirred at room temperature for 50 minutes.The excess solvent was removed under reduced pressure, giving the crude(R)-1-phenyl-N²-(tetrahydro-pyran-4-yl)-ethane-1,2-diamine TFA salt as apale yellow oil (849 mg).

Following general procedure A: crude(R)-1-phenyl-N²-(tetrahydro-pyran-4-yl)-ethane-1,2-diamine TFA salt(1.12 mmol), 1-Boc-4-piperidone (246 mg, 1.23 mmol) and NaBH(OAc)₃ (338mg, 1.59 mmol) in CH₂Cl₂ (7.5 ml) was stirred at room temperature for 17hours. Standard workup gave crude(3-{4-[(R)-1-phenyl-2-(tetrahydro-pyran-4-ylamino)-ethylamino]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester as a pale yellow oil (516 mg, quantitative).

To a 0° C. solution of the crude diamine (0.56 mmol) and pyridine (0.10ml, 1.2 mmol) in CH₂Cl₂ (5.5 ml) was added triphosgene (85 mg, 0.29mmol) and the reaction was stirred at 0° C. for 40 minutes. The reactionwas diluted with saturated aqueous NaHCO₃ (25 ml) and extracted withCH₂Cl₂ (20 ml×3). The organic solution was dried (Na₂SO₄), filtered andconcentrated under reduced pressure. Purification by flash columnchromatography on silica (CH₂Cl₂/MeOH, 32:1) gave4-[(R)-2-oxo-5-phenyl-3-(tetrahydro-pyran-4-yl)-imidazolidin-1-yl]-piperidine-1-carboxylicacid tert-butyl ester as a white foam (194 mg, 81%). ¹H NMR (CDCl₃) δ1.34-1.48 (m, 2H), 1.38 (s, 9H), 1.58-1.85 (m, 6H), 2.50-2.70 (m, 2H,3.08 (dd, 1H, J=8.4, 6.9 Hz), 3.43-3.53 (m, 2H), 3.64 (t, 1H, J=9.0 Hz),3.66-3.78 (m, 1H), 3.85-4.16 (m, 5H), 4.56 (dd, 1H, J=9.2, 7.0 Hz),7.24-7.38 (m, 5H).

Following general procedure C, the tert-butyl carbamate (194 mg, 0.45mmol) gave(R)-4-phenyl-3-piperidin-4-yl-1-(tetrahydro-pyran-4-yl)-imidazolidin-2-oneas a white foam (128 mg, 86%). ¹H NMR (CDCl₃) δ 1.07 (qd, 1H, J=12.4,4.3 Hz), 1.41-1.50 (m, 2H), 1.56-1.84 (m, 6H), 2.47 (td, 1H, J=12.3, 2.5Hz), 2.58 (td, 1H, J=12.0, 3.1 Hz), 2.84-2.92 (m, 1H), 3.02-3.09 (m,1H), 3.06 (dd, 1H, J=8.4, 6.9 Hz), 3.43-3.52 (m, 2H), 3.64 (t, 1H, J=8.9Hz), 3.69 (tt, 1H, J=11.9, 3.9 Hz), 3.94-4.10 (m, 3H), 4.60 (dd, 1H,J=9.5, 6.7 Hz), 7.28-7.37 (m, 5H).

Following general procedure B: a solution of the piperidine (128 mg,9.39 mmol), 2-(3-oxo-butyl)-isoindole-1,3-dione (173 mg, 0.80 mmol) andglacial AcOH (6 drops) in MeOH (2.0 ml) at 55° C. under nitrogen wasadded NaBH₃CN (80 mg, 1.27 mmol) and the reaction was stirred for 22hours. Standard workup and purification by flash column chromatographyon silica (CH₂Cl₂/MeOH, 29:1) gave the phthalimide as a white foam (126mg, 61%).

Following general procedure D, the phthalimide (126 mg, 0.24 mmol) gave(R)-3-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-4-phenyl-1-(tetrahydro-pyran-4-yl)-imidazolidin-2-oneas a colorless oil (90.3 mg, 95%). ¹H NMR (CDCl₃) δ 0.86 (d, 3H, J=6.6Hz), 1.00-1.92 (m, 12H), 1.99 and 2.12 (td, 1H, J=11.6, 2.2 Hz), 2.24and 2.37 (td, 1H, J=11.4, 2.2 Hz), 2.49-2.79 (m, 5H), 3.05 (t, 1H, J=7.2Hz), 3.43-3.52 (m, 2H), 3.54-3.64 and 4.00-4.10 (m, 1H), 3.63 (t, 2H,J=9.0 Hz), 3.94-4.03 (m, 2H), 4.59 (dd, 1H, J=9.2, 6.6 Hz), 7.28-7.37(m, 5H).

Following general procedure E: a solution of(R)-3-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-4-phenyl-1-(tetrahydro-pyran-4-yl)-imidazolidin-2-one(30.1 mg, 0.075 mmol), 6-chloro-2,4-dimethyl-nicotinic acidhydrochloride (22 mg, 0.099 mmol), EDCI (21 mg, 0.11 mmol), HOBT (17 mg,0.13 mmol) and NMM (22 μL, 0.20 mmol) in DMF (0.50 ml) was stirred atroom temperature for 18.5 hours. Standard workup and purification byflash column chromatography on silica (CH₂Cl₂/MeOH/NH₄OH, 32:1:0.17)gave COMPOUND 295 as a light yellow foam (32.9 mg, 77%). ¹H NMR (CDCl₃)δ 0.70-1.03 (m, 1H), 0.90 and 0.92 (d, 3H, J=6.6 Hz), 1.19-1.37 (m, 2H),1.45-1.76 (m, 7H), 1.86-2.12 (m, 1H), 2.33 and 2.34 (s, 3H), 2.35-3.00(m, 4H), 2.52 and 2.54 (s, 3H), 3.08-3.69 (m, 6H), 3.91-4.20 (m, 5H),7.11 and 7.12 (s, 1H), 7.20-7.37 (m, 5H), 8.11 and 8.31 (br s, 1H);ES-MS m/z 568 (M+H), 570 (M+H+2).

Example 296

Compound 2966-Chloro-2,4-dimethyl-N-(3-{4-[(R)-5-phenyl-3-(tetrahydro-pyran-4-yl)-2-thioxo-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-nicotinamide

COMPOUND 296 was prepared from4-[(R)-1-phenyl-2-(tetrahydro-pyran-4-ylamino)-ethylamino]-piperidine-1-carboxylicacid tert-butyl ester following similar chemistry as for COMPOUND 295except that thiophosgene was used in lieu of triphosgene. COMPOUND 296was isolated as a pale yellow foam. ¹H NMR (CDCl₃) δ 0.58-0.98 (m, 2H),0.92 and 0.94 (d, 3H, J=6.6 Hz), 1.23-2.23 (m, 9H), 2.30-2.79 (m, 4H),2.33 and 2.35 (s, 3H), 2.54 and 2.56 (s, 3H), 3.07-3.40 (m, 1H), 3.25(dd, 1H, J=9.6, 3.1 Hz), 3.45-3.69 (m, 3H), 3.86 (td, 1H, J=9.9, 2.5Hz), 3.91-4.05 (m, 2H), 4.09 and 4.22 (dd, 1H, J=9.9, 3.1 Hz), 4.42-4.58(m, 1H), 4.80 (tt, 1H, J=11.9, 4.4 Hz), 7.11-7.17 (m, 3H), 7.29-7.37 (m,3H), 8.42 and 8.68 (br s, 1H); ES-MS m/z 586 (M+H+2).

Example 297

Compound 2976-Chloro-2,4-dimethyl-N-(3-{4-[(R)-3-(1-methyl-1H-pyrrol-2-ylmethyl)-2-oxo-5-phenyl-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-nicotinamide

Following general procedure A: to a stirred solution of[(+/−)-3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester(942 mg, 3.49 mmol) in CH₂Cl₂ (15 ml) at rt was added2-((R)-2-amino-2-phenyl-ethyl)-isoindole-1,3-dione (930 mg, 3.49 mmol)and NaBH(OAc)₃ (935 mg, 4.19 mmol) and the resultant solution wasstirred at rt overnight. The resultant crude product (294 mg, yellowoil) was used directly in the next step.

Following general procedure C: to a stirred solution of the product fromlast step in CH₂Cl₂ (3 ml) at rt was added TFA (3 ml). The mixture wasstirred at rt for 2 h to give crude amine2-{(R)-2-[1-(3-amino-1-methyl-propyl)-piperidin-4-ylamino]-2-phenyl-ethyl}-isoindole-1,3-dione(1.68 g, 100%).

Following general procedure E: a solution of crude amine2-{(R)-2-[1-(3-amino-1-methyl-propyl)-piperidin-4-ylamino]-2-phenyl-ethyl}-isoindole-1,3-dione(450 mg, 1.07 mmol), 6-chloro-2,4-dimethyl-nicotinic acid (238 mg, 1.07mmol), EDCI (247 mg, 1.28 mmol), HOBT (174 mg, 1.28 mmol), and DIPEA(0.65 ml, 3.75 mmol) in CH₂Cl₂ (10 ml) was stirred overnight.Purification of the crude product by chromatography on silica gel(CH₂C₂/MeOH, 9:1) afforded6-chloro-N-(3-{4-[(R)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-phenyl-ethylamino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide(346 mg, 55%).

Following general procedure D: a solution of6-chloro-N-(3-{4-[(R)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-phenyl-ethylamino]-piperidin-1-yl}-butyl)-2,4-dimethyl-nicotinamide(194 mg, 0.33 mmol), hydrazine hydrate (0.05 ml ml, 0.1 mmol) in EtOH (2ml) was stirred at rt overnight. Purification of the crude product bychromatography on silica gel (CH₂Cl₂/MeOH/NH₄OH, 100:10:2) affordedN-{3-[4-((R)-2-Amino-1-phenyl-ethylamino)-piperidin-1-yl]-butyl}-6-chloro-2,4-dimethyl-nicotinamide(102 mg, 67%).

A solution ofN-{3-[4-((R)-2-Amino-1-phenyl-ethylamino)-piperidin-1-yl]-butyl}-6-chloro-2,4-dimethyl-nicotinamide(60 mg, 0.13 mmol) and 1-Methyl-1H-pyrrole-2-carbaldehyde (15 mg, 0.13mmol) in CH₃OH (2 ml) was stirred at rt for 2 h. The mixture was thencooled to 0° C. NaBH₄ (8 mg, 0.2 mmol) was added. The mixture wasstirred at this temperature for 20 min. NH₄Cl (aq. Sat. 1 ml) was thenadded and the mixture was extracted with CH₂Cl₂ (3×10 ml). The organiclayer was dried and concentrated. Purification of the residue bychromatography on silica gel (CH₂Cl₂/MeOH, 9:1) afforded6-chloro-2,4-dimethyl-N-[3-(4-{(R)-2-[(1-methyl-1H-pyrrol-2-ylmethyl)-amino]-1-phenyl-ethylamino}-piperidin-1-yl)-butyl]-nicotinamide(57 mg, 79%).

To a 0° C. solution of the crude diamine (57 mg, 0.1 mmol) and pyridine(0.02 ml, 0.25 mmol) in CH₂Cl₂ (2 ml) was added triphosgene (16 mg, 0.05mmol) and the resulting solution was stirred at 0° C. for 30 minutesfollowed by 1 h at rt. Standard work-up and purification gave COMPOUND297 (20 mg, 35%) as a yellow solid. ¹H NMR (CDCl₃) mixture ofdiastereoisomers δ 0.77-2.20 (m, 10H), 2.26-2.80 (m, 10H), 3.10-4.00 (m,7H), 4.01-4.25 (m, 1H), 4.35 (s, 2H), 5.97 (s, 2H), 6.57 (s, 1H), 7.16(s, 1H), 7.18-7.33 (m, 5H), 7.95-8.13 (m, 1H); ¹³C NMR (CDCl₃) δ 13.41,13.90, 19.21, 22.52, 29.52, 30.54, 30.81, 31.04, 31.88, 32.06, 33.16,34.20, 39.95, 40.22, 40.57, 43.68, 44.36, 52.04, 52.45, 52.59, 55.58,55.83, 59.94, 60.60, 106.98, 109.91, 117.16, 122.98, 123.41, 124.88,126.54, 127.13, 127.66, 128.35, 129.15, 130.04, 133.01, 133.12, 143.20,143.36, 147.91, 148.02, 150.56, 155.73, 160.54, 167.35, 167.84; ES-MSm/z 577 (M+1).

Example 298

Compound 2986-Chloro-N-{3-[4-((R)-3-isopropyl-2-oxo-5-phenyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-2,4-dimethyl-nicotinamide

Following general procedure A,N-{3-[4-((R)-2-amino-1-phenyl-ethylamino)-piperidin-1-yl]-butyl}-6-chloro-2,4-dimethyl-nicotinamide(see EXAMPLE 297) and acetone gave the desired amine. To a 0° C.solution of the crude diamine and pyridine in CH₂Cl₂ (2 ml) was addedtriphosgene and the resulting solution was stirred at 0° C. for 30minutes followed by 1 h at rt. Standard work-up and purification gaveCOMPOUND 298 as a yellow solid. ¹H NMR (CDCl₃) mixture ofdiastereoisomers δ 0.77-2.20 (m, 10H), 2.26-2.80 (m, 10H), 3.10-4.00 (m,7H), 4.01-4.25 (m, 1H), 4.35 (s, 2H), 5.97 (s, 2H), 6.57 (s, 1H), 7.16(s, 1H), 7.18-7.33 (m, 5H), 7.95-8.13 (m, 1H); ¹³C NMR (CDCl₃) δ 13.41,13.90, 19.21, 22.52, 29.52, 30.54, 30.81, 31.04, 31.88, 32.06, 33.16,34.20, 39.95, 40.22, 40.57, 43.68, 44.36, 52.04, 52.45, 52.59, 55.58,55.83, 59.94, 60.60, 106.98, 109.91, 117.16, 122.98, 123.41, 124.88,126.54, 127.13, 127.66, 128.35, 129.15, 130.04, 133.01, 133.12, 143.20,143.36, 147.91, 148.02, 150.56, 155.73, 160.54, 167.35, 167.84; ES-MSm/z 577 (M+H).

Example 299

Compound 299N-(3-{4-[(R)-3-(2-Amino-phenyl)-2-oxo-5-phenyl-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-6-chloro-2,4-dimethyl-nicotinamide

To a degassed solution of ((R)-2-amino-1-phenyl-ethyl)-carbamic acidtert-butyl ester (400 mg, 1.69 mmol) in toluene (10 ml), was added2-nitroiodobenzene (423 mg, 1.69 mmol), Pd₂ (dba)₃ (31 mg, 0.34 mmol),4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (39 mg, 0.68 mmol) andCs₂CO₃ (551 mg, 1.69 mmol). The mixture was heated at 110° C. for 24 h.It was then concentrated and the residue was purified using columnchromatography (4:1, Hexanes/EtOAc) to give[(R)-2-(2-nitro-phenylamino)-1-phenyl-ethyl]-carbamic acid tert-butylester (390 mg, 64%).

Following general procedure C with[(R)-2-(2-nitro-phenylamino)-1-phenyl-ethyl]-carbamic acid tert-butylester then general procedure A with the resulting amine and[(R)-3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl esterafforded the desired diamine. The diamine was treated with triphosgeneunder standard conditions to afford(3-{4-[(R)-3-(2-nitro-phenyl)-2-oxo-5-phenyl-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester.

To a solution of(3-{4-[(R)-3-(2-nitro-phenyl)-2-oxo-5-phenyl-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (180 mg, 0.334 mmol) in CH₃OH (3 ml) was addedPd/C (20 mg, 50%). The mixture was hydrogenated under H₂ (2 atm.) for 10min. Filtration and concentration gave(3-{4-[(R)-3-(2-amino-phenyl)-2-oxo-5-phenyl-imidazolidin-1-yl]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (160 mg, 94%). Treatment with TFA (1 ml) andCH₂Cl₂ (1 ml) according to general procedure C gave(R)-3-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-1-(2-amino-phenyl)-4-phenyl-imidazolidin-2-one(114 mg, 94%).

Following general procedure E: a solution of(R)-3-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-1-(2-amino-phenyl)-4-phenyl-imidazolidin-2-one(57 mg, 0.14 mmol), 6-chloro-2,4-dimethylnicotinic acid (34 mg, 0.30mmol), EDCI (33 mg, 0.14 mmol), HOBT (19 mg, 0.14 mmol), and NEt₃ (0.06ml, 0.40 mmol) in CH₂Cl₂ (2.0 ml) was stirred overnight. Purification ofthe crude product by column chromatography on silica gel (CH₂Cl₂/MeOH,9:1) afforded COMPOUND 299 (51 mg, 63%) as a white foam (mixture ofrotamers). ¹H NMR (CDCl₃) δ 0.80-1.25 (m, 4H), 1.26-2.20 (m, 6H),2.28-2.80 (m, 9H), 3.10-4.49 (m, 7H), 6.71-6.78 (m, 2H), 6.99-7.12 (m,3H), 7.27-7.45 (m, 5H), 8.15 (s, 0.44H), 6.30 (s, 0.56H); ES-MS m/z 575(M+H).

Example 300

Compound 3006-Chloro-2,4-dimethyl-N-{3-[4-((R)-2-oxo-3-phenyl-5-propyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-nicotinamide

A solution of D-norvaline (2.05 g, 17.5 mmol) and Boc₂O (3.55 g, 16.3mmol) in 1M NaOH (25 ml) and t-BuOH (25 ml) was stirred at roomtemperature for 3.5 hours. The organic solvent was removed under reducedpressure, the remaining aqueous solution was adjusted to pH 2 by theaddition of 4M HCl and the mixture was extracted with CHCl₃ (30 ml×3).The combined organic solution was dried (Na₂SO₄), filtered andconcentrated under reduced pressure, giving crude(R)-2-tert-butoxycarbonylamino-pentanoic acid as a colorless oil (3.55g, 100%).

To a 0° C. solution of the crude carboxylic acid (652 mg, 3.00 mmol) andNMM (0.50 ml, 4.5 mmol) in THF (12 ml) was added isobutyl chloroformate(0.45 ml, 3.5 mmol) and the resulting mixture was stirred at 0° C. for 5minutes. A solution of aniline (0.45 ml, 4.9 mmol) in THF (3 ml) wasthen added dropwise. The reaction was warmed to room temperature andstirred for 66 hours. The reaction was diluted with 1M HCl (30 ml) andwas extracted with Et₂O (25 ml×3). The organic solution was washed withbrine (50 ml), was dried (Na₂SO₄), filtered and concentrated underreduced pressure, giving crude ((R)-1-phenylcarbamoyl-butyl)-carbamicacid tert-butyl ester as an oily, light yellow foam.

A solution of the crude tert-butyl carbamate (3.00 mmol) and TFA (3.0ml) in CH₂Cl₂ (15 ml) was stirred at room temperature for 55 minutes.The reaction was made basic with 1M NaOH (50 ml) and was extracted withCHCl₃ (25 ml×3). The combined organic solution was dried (Na₂SO₄),filtered and concentrated under reduced pressure. Purification by flashcolumn chromatography on silica (CH₂Cl₂/MeOH, 9:1) gave(R)-2-amino-pentanoic acid phenylamide as a yellow oil (265 mg, 46%). ¹HNMR (CDCl₃) δ 0.97 (t, 3H, J=7.0 Hz), 1.37-1.70 (m, 5H), 1.86-1.99 (m,1H), 3.46-3.55 (m, 1H), 7.09 (t, 1H, J=7.3 Hz), 7.32 (t, 2H, J=7.5 Hz),7.60 (d, 2H, J=7.9 Hz), 9.48 (br s, 1H).

A solution of the amide (265 mg, 1.38 mmol) and BH₃·THF (1.0M in THF,5.0 ml, 5.0 mmol) in THF (5.0 ml) was stirred at reflux under nitrogenfor 15.5 hours. The reaction was cooled, quenched by the carefuladdition of 6M HCl (8 ml) and the mixture was stirred at 65° C. foranother 3 hours. Once cooled, the reaction was made basic with 1.7M NaOH(30 ml) and was extracted with CH₂Cl₂ (25 ml×3). The organic solutionwas dried (Na₂SO₄), filtered and concentrated under reduced pressure.Purification by flash column chromatography on silica(CH₂Cl₂/MeOH/NH₄OH, 29:1:0.15, increased to 19:1:0.2) gave (R)—N¹-phenyl-pentane-1,2-diamine as a yellow oil (204 mg, 83%). ¹H NMR(CDCl₃) δ 0.95 (t, 3H, J=6.6 Hz), 1.25-1.54 (m, 6H), 2.81-2.90 (m, 1H),2.95-3.04 (m, 1H), 3.15-3.24 (m, 1H), 4.12 (br s, 1H), 6.63 (d, 2H,J=7.9 Hz), 6.69 (t, 1H, J=7.5 Hz), 7.17 (t, 2H, J=7.7 Hz).

Following general procedure A: the amine (204 mg, 1.14 mmol),1-Boc-4-piperidone (232 mg, 1.16 mmol) and NaBH(OAc)₃ (345 mg, 1.63mmol) in CH₂Cl₂ (7.5 ml) was stirred at room temperature for 17.5 hours.Standard workup gave crude4-((R)-1-phenylaminomethyl-butylamino)-piperidine-1-carboxylic acidtert-butyl ester as a yellow oil (460 mg).

To a 0° C. solution of the secondary amine (1.14 mmol) and pyridine(0.20 ml, 2.5 mmol) in CH₂Cl₂ (12 ml) was added triphosgene (174 mg,0.59 mmol) and the resulting yellow solution was stirred at 0° C. for 60minutes. The reaction was diluted with 0.5M HCl (30 ml) and extractedwith CH₂Cl₂ (25 ml×2). The organic solution was dried (Na₂SO₄), filteredand concentrated under reduced pressure. Purification by flash columnchromatography on silica (CH₂Cl₂/Et₂O, 14:1, increased to 9:1) gave4-((R)-2-oxo-3-phenyl-5-propyl-imidazolidin-1-yl)-piperidine-1-carboxylicacid tert-butyl ester as an oily, white foam (405 mg, 92%). ¹H NMR(CDCl₃) δ 0.96 (t, 3H, J=7.2 Hz), 1.23-1.58 (m, 3H), 1.46 (s, 9H),1.65-1.97 (m, 5H), 2.68-2.83 (m, 2H), 3.42 (dd, 1H, J=8.7, 5.2 Hz),3.68-3.86 (m, 2H), 3.86 (t, 1H, J=9.0 Hz), 4.11-4.31 (m, 2H), 7.00 (t,1H, J=7.3 Hz), 7.31 (t, 2H, J=8.0 Hz), 7.51 (d, 2H, J=8.0 Hz).

Following general procedure C, the tert-butyl carbamate (405 mg, 1.05mmol) gave the crude piperidine as a yellow oil (311 mg, quantitative).

Following general procedure B: a solution of(R)-1-phenyl-3-piperidin-4-yl-4-propyl-imidazolidin-2-one (152 mg, 0.53mmol), 2-(3-oxo-butyl)-isoindole-1,3-dione (230 mg, 1.06 mmol), NaBH₃CN(108 mg, 1.72 mmol) and glacial AcOH (8 drops) in MeOH (2.5 ml) wasstirred at 60° C. for 16.5 hours. Standard workup and purification byflash column chromatography on silica (CH₂Cl₂/MeOH, 29:1) gave2-{3-[4-((R)-2-oxo-3-phenyl-5-propyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-isoindole-1,3-dione,contaminated with alcohol resulting from reduction of excess ketone (302mg).

Following general procedure D, the phthalimide gave the primary amine asa light yellow oil (92.3 mg, 49%). ¹H NMR (CDCl₃) δ 0.96 (t, 3H, J=7.2Hz), 0.96 and 0.97 (d, 3H, J=6.6 Hz), 1.23-2.04 (m, 12H), 2.17-2.28 (m,1H), 2.41-2.52 (m, 1H), 2.67-2.91 (m, 5H), 3.42 (dd, 1H, J=8.7, 4.8 Hz),3.63-3.80 (m, 2H), 3.87 and 3.88 (t, 1H, J=9.0 Hz), 7.00 (t, 1H, J=7.1Hz), 7.31 (t, 2H, J=8.0 Hz), 7.52 (d, 2H, J=7.8 Hz).

Following general procedure E: a solution of the primary amine (46.1 mg,0.13 mmol), 6-chloro-2,4-dimethylnicotinic acid (30 mg, 0.16 mmol), EDCI(34 mg, 0.18 mmol), HOBT (25 mg, 0.18 mmol) and NMM (35 μL, 0.32 mmol)in DMF (0.85 ml) was stirred at room temperature for 15.5 hours.Standard workup and purification by flash column chromatography onsilica (CH₂Cl₂/MeOH, 19:1, increased to 9:1) gave COMPOUND 300 as ayellow foam (56.2 mg, 83%). ¹H NMR (CDCl₃) δ 0.92 and 0.93 (t, 3H, J=6.8Hz), 1.06 and 1.09 (d, 3H, J=7.1 Hz), 1.23-1.95 (m, 10H), 2.23-2.35 (m,1H), 2.33 (s, 3H), 2.53 (s, 3H), 2.59-2.71 (m, 1H), 2.81-3.00 (m, 3H),3.27-3.50 (m, 2H), 3.40 (dd, 1H, J=8.6, 4.4 Hz), 3.66-3.94 (m, 2H), 3.85and 3.86 (t, 1H, J=8.5 Hz), 6.99-7.05 (m, 2H), 7.32 (t, 2H, J=8.1 Hz),7.49 (d, 2H, J=8.0 Hz), 8.11 (br s, 1H); ES-MS m/z 526 (M+H), 528(M+H+2). Anal. Calcd. for C₂₉H₄₀ClN₅O₂·0.2CH₂Cl₂: C, 64.58; H, 7.50; N,12.89. Found: C, 64.59; H, 7.57; N, 12.83.

Example 301

Compound 3014-[(S)-3-(1-{3-[(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-4-methoxymethyl-2-oxo-imidazolidin-1-ylmethyl]-benzoicacid methyl ester

(R)-2-tert-Butoxycarbonylamino-3-hydroxy-propionic acid methyl ester(2.2 mg, 10 mmol) was dissolved in THF (20 ml). Imidazole (818 mg, 12mmol) and TBDPS chloride (2.9 ml, 11 mmol) were added. The mixture wasstirred at rt overnight. The mixture was then partitioned between CH₂Cl₂and water (30 ml/30 ml). The organic layer was concentrated and theresidue was purified by column chromatography (6/1, Hexanes/EtOAc) togive(R)-2-tert-butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-propionicacid methyl ester (3.3 g, 72%).

(R)-2-tert-Butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-propionicacid methyl ester (3.3 g, 7.2 mmol) was dissolved in ether (25 ml). Thesolution was cooled to 0° C. in an ice bath. LiBH₄ (2.32 g, 10 mmol) wasadded in small portions. The resultant mixture was stirred for 20 min atthis temperature before warming to rt and was stirred for an additional60 min. The mixture was then transferred dropwise to an aqueous HClsolution (2%, 10 ml). The aqueous layer was extracted with EtOAc (20ml×2). The organic layer was dried over Na₂SO₄ and concentrated to givethe desired alcohol (2.6 g, 81%).

The alcohol (2.6 g, 5.85 mmol) was subjected to general Mitsunobureaction conditions using phthalimide (1.29 g, 8.5 mmol), DEAD (2.3 ml,14.6 mmol) and Ph₃P (4.6 g, 17.4 mmol) in THF (60 ml). The reaction gave[(S)-2-(tert-butyl-diphenyl-silanyloxy)-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-ethyl]-carbamicacid tert-butyl ester (2.3 g, 63%).

[(S)-2-(tert-Butyl-diphenyl-silanyloxy)-1-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-ethyl]-carbamicacid tert-butyl ester (1.1 g, 1.92 mmol) was treated with hydrazinehydrate (0.5 ml, 9 mmol) in EtOH (5 ml) at rt over night to give[(S)-1-aminomethyl-2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-carbamicacid tert-butyl ester (640 mg, 75%).

[(S)-1-Aminomethyl-2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-carbamicacid tert-butyl ester (640 mg, 1.44 mmol) was stirred with methyl4-formylbenzoate (237 mg, 1.44 mmol) in CH₃OH (3 ml) at rt for 2 h.NaBH₄ (58 mg, 1.44 mmol) was added. The mixture was stirred at rt for 20min. Several drops of saturated aqueous NH₄Cl were added. The mixturewas then partitioned between CH₂Cl₂ and water (20 ml/20 ml). The organiclayer was concentrated to give4-{[(S)-2-tert-butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-propylamino]-methyl}-benzoicacid methyl ester (650 mg, 76%).

According to general procedure C,4-{[(S)-2-tert-butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-propylamino]-methyl}-benzoicacid methyl ester (650 mg, 1.1 mmol) was treated with TFA (2 ml) andCH₂Cl₂ (2 ml) to give the deprotected amine, which was reacted with4-BOC piperidone (237 mg, 1.2 mmol) and NaHB(OAc)₃ (362 mg, 1.5 mmol) inCH₂Cl₂ (5 ml) according to general procedure A, to give4-{(S)-2-(tert-butyl-diphenyl-silanyloxy)-1-[(4-methoxycarbonyl-benzylamino)-methyl]-ethylamino}-piperidine-1-carboxylicacid methyl ester (305 mg, 42% over 2 steps). This diamine was subjectedto standard cyclization with triphosgene (68 mg, 0.9 mmol) and pyridine(0.1 ml, 1 mmol) in CH₂Cl₂ (2 ml) to give4-[(S)-5-(tert-butyl-diphenyl-silanyloxymethyl)-3-(4-methoxycarbonyl-benzyl)-2-oxo-imidazolidin-1-yl]-piperidine-1-carboxylicacid methyl ester (380 mg, containing impurity).

4-[(S)-5-(tert-Butyl-diphenyl-silanyloxymethyl)-3-(4-methoxycarbonyl-benzyl)-2-oxo-imidazolidin-1-yl]-piperidine-1-carboxylicacid methyl ester (380 mg, containing impurity) was dissolved in THF (3ml) and treated with TBAF (283 mg, 1.1 mmol) at rt for 1 h. The mixturewas then partitioned between CH₂Cl₂ and water (10 ml/10 ml). The organiclayer was dried over Na₂SO₄ and concentrated. The residue was purifiedby column chromatography (EtOAc) to give the intermediate alcohol (170mg). This alcohol was dissolved in DMF (2 ml) and cooled in an ice bath.NaH (22 mg, 0.6 mmol, 60% in oil) was added and the mixture was stirredat rt for 10 min. MeI (0.05 ml, 0.8 mmol) was added and the mixturestirred over night and then concentrated. The residue was purified bycolumn chromatography (EtOAc) to give4-[(S)-3-(4-methoxycarbonyl-benzyl)-5-methoxymethyl-2-oxo-imidazolidin-1-yl]-piperidine-1-carboxylicacid methyl ester (87 mg, 49%).

According to general procedure C,4-[(S)-3-(4-methoxycarbonyl-benzyl)-5-methoxymethyl-2-oxo-imidazolidin-1-yl]-piperidine-1-carboxylicacid methyl ester (87 mg, 0.18 mmol) was treated with TFA/CH₂Cl₂ (2 ml/2ml). Following general procedure B, the resultant free amine and2-(3-oxo-butyl)-isoindole-1,3-dione gave the desired product which wasthen subjected to deprotection according to general procedure D to give4-{(S)-3-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-4-methoxymethyl-2-oxo-imidazolidin-1-ylmethyl}-benzoicacid methyl ester (40 mg).

According to general procedure E,4-{(S)-3-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-4-methoxymethyl-2-oxo-imidazolidin-1-ylmethyl}-benzoicacid methyl ester (40 mg) and 6-chloro-2,4-dimethyl-nicotinic acid gave4-[(S)-3-(1-{3-[(6-chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-4-methoxymethyl-2-oxo-imidazolidin-1-ylmethyl]-benzoicacid methyl ester (32 mg, 60%).

4-[(S)-3-(1-{3-[(6-Chloro-2,4-dimethyl-pyridine-3-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-4-methoxymethyl-2-oxo-imidazolidin-1-ylmethyl]-benzoicacid methyl ester (32 mg, 0.045 mmol) was dissolved in CH₃OH (1 ml).NaOH (0.05 ml, 10 N, 0.47 mmol) was added and the mixture was heated at60° C. for 3 h. It was then concentrated to remove CH₃OH and water (2ml) was added. The pH of the solution was adjusted to 6 using 1 N HClsolution. It was then concentrated to dryness and the residue wasextracted with CH₂Cl₂/CH₃OH (4/1, 10 ml×3). The combined extracts wereconcentrated to give COMPOUND 301 as white solid (26 mg, 94%). ¹H NMR(CD₃OD) δ 1.30-1.45 (m, 3H), 1.70-2.80 (m, 1H), 2.85-4.00 (m, 18H, CH₃OHsignal), 4.10-4.45 (m, 2H), 7.30-7.40 (m, 2H), 7.95-8.00 (m, 2H); ES-MSm/z 586 (M+1).

Example 302

Compound 302 4,6-Dimethyl-pyrimidine-5-carboxylic acid{(S)-3-[4-((R)-2-cyanoimino-5-phenyl-3-pyridin-3-ylmethyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-amide

To a 0° C. solution of (R)-(−)-2-phenylglycinyl (3.03 g, 22.1 mmol) andNEt₃ (4.50 ml, 32.3 mmol) in THF (55 ml) was added Boc₂O (4.82 g, 22.1mmol) and the resulting white suspension was stirred at 0° C. for 1 hourgiving crude ((R)-2-hydroxy-1-phenyl-ethyl)-carbamic acid tert-butylester as a white powder (4.75 g, 91%) following an acidic work-up.

To a 0° C. solution of the alcohol (4.75 g, 20.0 mmol), phthalimide(3.32 g, 22.6 mmol) and PPh₃ (6.30 g, 24.0 mmol) in THF (130 ml) undernitrogen was added dropwise DEAD (3.3 ml, 21.0 mmol). The resultinglight yellow solution was stirred at room temperature for 3 hours, andthen the solvent was removed under reduced pressure, giving crude[(R)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1-phenyl-ethyl]-carbamicacid tert-butyl ester as a mixture with triphenylphosphine oxide.

A solution of the crude phthalimide and hydrazine hydrate (10.0 ml, 177mmol) in EtOH (200 ml) was stirred at reflux for 1 hour. Once cooled,the mixture was concentrated under reduced pressure. The residue wassuspended in 1.5M HCl (200 ml) and washed with CH₂Cl₂ (50 ml×3). Theorganic solution was extracted with 4M HCl (50 ml×2). The combinedaqueous extracts were made basic with 10M NaOH (100 ml) and extractedwith CH₂Cl₂ (50 ml×4). This organic solution was dried (Na₂SO₄),filtered and concentrated under reduced pressure. Purification gave((R)-2-amino-1-phenyl-ethyl)-carbamic acid tert-butyl ester as anoff-white solid (2.41 g, 51% over 2 steps).

A solution of 3-pyridinecarboxaldehyde (49 mg, 0.46 mmol) and((R)-2-amino-1-phenyl-ethyl)-carbamic acid tert-butyl ester (108 mg,0.457 mmol) in MeOH (4.6 ml) was stirred at room temperature for 1 hour.NaBH₄ (17 mg, 0.45 mmol) was added and the mixture stirred at roomtemperature for 50 minutes. Standard work up gave the crude carbamate.Using general procedure C with the substrate followed by generalprocedure A with the resulting amine and[(S)-3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester (161mg, 0.595 mmol) afforded the desired diamine.

Using general procedure C,[3-(4-{1-phenyl-2-[(pyridin-3-ylmethyl)-amino]-ethylamino}-piperidin-1-yl)-butyl]-carbamicacid tert-butyl ester (80 mg, 0.166 mmol) and a mixture of CH₂Cl₂ andTFA (1:1, 1 ml) gave the desired amine (46 mg, 73%).

Using general procedure E, the amine above (46 mg, 0.12 mmol) and4,6-dimethyl-pyrimidine-5-carboxylic acid (18 mg, 0.12 mmol) affordedthe corresponding amide (32 mg, 52%).

The amide above (32 mg, 0.06 mmol) and dimethyl cyanoiminothiocarbonate(6 mg, 0.036 mmol) in methanol (1 ml) were heated at 60° C. for 18 hunder N₂. Standard work-up and purification gave COMPOUND 302 as a cisand trans mixture. ¹H NMR (CDCl₃) δ 0.90-0.94 (m, 3H), 1.55-1.57 (m,2H), 1.67-1.88 (m, 3H), 2.36-2.48 (m, 3H), 2.52 (s, 6H), 2.67-2.76 (m,2H), 2.85-3.05 (m, 1H), 3.20-3.26 (m, 1H), 3.46-3.54 (m, 1H), 3.67-3.85(m, 2H), 4.09-4.77 (m, 4H), 7.07-7.16 (m, 2H), 7.33-7.35 (m, 4H), 7.65and 7.58 (two d, 1H, J=7.8 Hz), 7.85-7.91 (m, 1H), 8.46-8.55 (m, 2H),8.94 and 8.97 (two s, 1H); ¹³C NMR (CDCl₃) δ 13.46, 13.78, 22.40, 29.66,30.10, 31.80, 32.06, 32.16, 32.41, 39.81, 39.89, 43.48, 43.83, 45.38,46.03, 47.33, 51.85, 52.36, 52.51, 52.66, 53.83, 53.96, 54.75, 55.74,57.00, 60.20, 60.36, 116.50, 124.01, 124.27, 125.94, 126.58, 128.58,129.13, 129.27, 129.68, 131.26, 131.34, 133.03, 136.17, 136.35, 141.79,149.41, 149.76, 150.09, 157.81, 158.48, 160.78, 163.53, 163.65, 166.42;ES-MS m/z 588.5 (M+Na).

Example 303

Compound 3036-Chloro-2,4-dimethyl-N—((S)-3-{4-[(R)-4-phenyl-2-(pyridin-3-ylamino)-oxazolidin-3-yl]-piperidin-1-yl}-butyl)-nicotinamide

Following general procedure A,[(S)-3-(4-oxo-piperidin-1-yl)-butyl]-carbamic acid tert-butyl ester (709mg, 2.63 mmol) and (R)-(−)-2-phenylglycinyl (343 mg, 2.50 mmol) provided{3-[4-(2-hydroxy-1-phenyl-ethylamino)-piperidin-1-yl]-butyl}-carbamicacid tert-butyl ester (600 mg, 61%).

To a solution of above product (170 mg, 0.435 mmol) in CH₂Cl₂ (2 ml) wasadded pyridine-3-isocyanate (54.7 mg, 0.456 mmol) and the mixture wasstirred at room temperature overnight. The mixture was concentratedunder reduced pressure and purified by column chromatography on silicagel (95:5:1, CH₂Cl₂/MeOH/NH₄OH) to provide(3-{4-[1-(2-hydroxy-1-phenyl-ethyl)-3-pyridin-3-yl-ureido]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (222 mg, 100%).

To a solution of above product (222 mg, 0.435 mmol) in CH₂Cl₂ (3 ml) andtriethylamine (67, mg, 0.663 mmol) was added methanesulfonylchloride (53mg, 0.464 mmol) and the mixture was stirred at room temperature for 3 hand then heated at reflux for 1 h. The mixture was concentrated underreduced pressure and purified by column chromatography on silica gel(95:5:1, CH₂Cl₂/MeOH/NH₄OH) to provide(3-{4-[4-phenyl-2-(pyridin-3-ylamino)-oxazolidin-3-yl]-piperidin-1-yl}-butyl)-carbamicacid tert-butyl ester (128 mg, 59%).

Following general procedure C, the above product gave{3-[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-4-phenyl-oxazolidin-2-ylidene}-pyridin-3-yl-amine(82.1 mg, 80%).

Following general procedure E, the above product (82.1 mg, 0.209 mmol)and 6-chloro-2,4-dimethyl-nicotinic acid HCl salt (48.6 mg, 0.219 mmol)gave COMPOUND 303 (102 mg, 87%). ¹H NMR (CDCl₃) δ 0.88-1.01 (m, 2H),0.93 (d, 3H, J=6.6 Hz), 1.42 (d, 1H, J=12.3 Hz), 1.49-1.55 (m, 1H), 1.91(d, 1H, J=12.0 Hz), 2.20 (t, 1H, J=11.1 Hz), 2.32 (s, 3H), 2.39 (t, 1H,J=11.1 Hz), 2.53 (s, 3H), 2.56 (m, 1H), 2.72-2.81 (m, 2H), 3.14-3.22 (m,1H), 3.81-3.90 (m, 2H), 4.05 (dd, 1H, J=8.4, 3.9 Hz), 4.24 (dd, 1H,J=8.4, 3.9 Hz), 4.53 (t, 1H, J=8.4 Hz), 7.07 (s, 1H), 7.12-7.16 (m, 1H),7.26-7.46 (m, 6H), 8.16 (br s, 1H), 8.29 (d, 1H, J=6.0 Hz), 8.33 (br s,1H); ¹³C NMR (CDCl₃) δ 13.57, 19.18, 22.53, 29.11, 31.79, 31.94, 39.84,43.72, 52.03, 53.11, 58.15, 60.51, 73.92, 122.92, 123.52, 126.45,128.87, 129.50, 130.59, 133.28, 142.09, 143.19, 144.36, 146.17, 148.23,150.38, 154.14, 155.75, 167.26; ES-MS m/z 562 (M+H). Anal Calcd. forC₃₁H₃₇N₆ClO₂·0.2CH₂Cl₂: C, 64.82; H, 6.52; N, 14.54. Found: C, 64.71; H,6.70; N, 14.59.

Example 304 Cell Fusion Assay

The assay measures the ability of a test compound to inhibit gp120 andCD4/CCR5-dependent cell-cell fusion. The assay uses two cell lines, 1)CHO-tat cell line that expresses the viral gp120 from a R5 using virus(JR-FL) and the HIV tat proteins, 2) P4-CCR5 cell line that expresseshuman CD4 and CCR5 on the surface and carries a β-galactosidaseconstruct under the control of the retroviral promotor LTR. Once fusionof these two cell lines occurs, the tat protein from the CHO cell linetrans-activates the reporter gene β-galactosidase in the P4-CCR5 cellline. In a 96 well format, 1×10⁴ cells of each cell line are plated perwell in the presence or absence of test compound. The cells are thenincubated at 37° C., 5% CO₂ for 18-24 hours. The β-galactosidaseactivity in each well is measured by the addition of a luminescencesubstrate (Gal-Screen substrate, Applied Biosystems) and luminescencemonitored with a Victor 2 plate reader (Wallac). The ability of testcompounds to inhibit fusion is indicated by a decrease inβ-galactosidase activity. Results are reported as the concentration oftest compound required to inhibit 50% of the β-galactosidase activity inthe test controls.

When tested in the assay described above, many compounds of theinvention exhibited IC₅₀'s in the range of 0.01 nM to 100 nM.

Example 305 Assay for Inhibition of RANTES Binding to HEK293F.CCR5 Cells

For the competition binding studies, a concentration range of antagonistwas incubated for 45 minutes at room temperature in binding buffer (50mM HEPES, 5 mM mgCl₂, 1 mM CaCl₂, 0.2% BSA pH 7.4) with 8 μg ofHEK293F.CCR5 cell membrane and 50 pM ¹²⁵I-RANTES (Perkin Elmer, 81400GBq/mmol) in Milipore GF-B filter plates. Unbound ¹²⁵I-RANTES wasremoved by washing with cold 50 mM HEPES, 0.5 M NaCl pH 7.4. Compoundswere tested at a concentration range of 10000-0.6 nM. The 50% inhibitoryconcentration (IC₅₀ value) was defined as the concentration of testcompound required to inhibit RANTES binding by 50% relative to untestedcontrols.

When tested in the assay described above, many of the compounds of theinvention exhibited IC₅₀'s in the range of 1 nM to 500 nM.

Example 306 Assay for Inhibition of HIV-1 Using PBMC and R5

Performed as described in literature (Inhibition of T-tropic HIV strainsby selective antagonization of the chemokine receptor CXCR4. 1997— D.Schols, S. Struyf, J. Van Damme, J. A. Esté, G. Henson & E. De Clercq.J. Exp. Med. 186, 1383-1388.)

The method were as follows:

PBMC from healthy donors were isolated by density gradientcentrifugation and stimulated with PHA at 1 μg/ml (Sigma Chemical Co.,Bornem, Belgium) for 3 days at 37° C. The activated cells(PHA-stimulated blasts) were washed three times with PBS, and viralinfections were performed. The cells were seeded in 48-well plates(5×10⁵ cells per well in 200 uL culture medium) and pre-incubated for 15min with compounds at different concentrations. Then 500 pg p24 viralAg/well of CCR5-using viruses was added. The HIV-1 R5 strains BaL,SF-162, ADA, and JR-FL were all obtained through the Medical ResearchCouncil AIDS reagent project (Herts, UK).

HIV-infected or mock-infected PHA-stimulated blasts were then furthercultured in the presence of 25 U/ml of IL-2 and supernatant wascollected at days 8-10, and HIV-1 core antigen in the culturesupernatant was analyzed by the p24 Ag ELISA kit from DuPont-MerckPharmaceutical Co. (Wilmington, Del.).

When tested in the assay described above, many compounds of theinvention exhibited IC₅₀'s in the range of 0.01 nM to 50 μM.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative, and are not to be takenas limitations upon the scope of the invention. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof. U.S. patents and publications referenced herein areincorporated by reference.

1. A compound having the formula 2

and pharmaceutically acceptable salts thereof; wherein W is oxygen,sulfur, NR², NOR², NCN, NSO₂R², NAc, NNO₂, CRNO₂, NCOR², C(CN)₂ or CRCN;V is O, S, N-L-R³, or CR-L-R³; L is a bond or a (CR₂)_(m) linkeroptionally having one carbon of (CR₂)_(m) replaced by a group selectedfrom O, S, and NR, and m is 1-3; R¹ is an optionally substituted aryl orheteroaryl; R² is H, an optionally substituted alkyl, a carbocyclicring, a heterocyclic ring, an aryl, or a heteroaryl; R³ is H; anoptionally substituted alkyl, alkenyl or alkynyl; hydroxy, alkoxy,cyano, amino, amido, COR², CO₂R², S═(O)_(p)R², CR═N—OR, O(CR₂)CN,NR—COR², SR²; a carbocyclic ring, a heterocyclic ring, an aryl, or aheteroaryl; and R is H, C₁₋₆ alkyl, or C₃₋₆ cycloalkyl; wherein in eachsaid optionally substituted alkyl, alkenyl or alkynyl, a carbon may beoptionally substituted with halo, N, O, or S, and/or replaced with N, Oor S; and each carbocyclic ring, heterocyclic ring, aryl or heteroarylmay be optionally substituted and/or fused with a carbocyclic, aryl,heterocyclic, or heteroaryl ring.
 2. The compound of claim 1, wherein R¹is phenyl, pyrimidinyl or pyridinyl, each optionally substituted withhalo, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl,or N-oxide.
 3. The compound of claim 1, wherein R² is phenyl, thienyl,or imidazolyl each optionally substituted with halo, cyano, alkoxy,heterocyclyl, aryl, heteroaryl, or N-oxide; or alkyl or cycloalkyl, eachof which may be optionally substituted with halo, cyano, OR, SR, orN(R)_(m), or in which one carbon may be optionally replaced with N, O,or S.
 4. The compound of claim 1, wherein R³ is H, C₁₋₁₀ straight orbranched alkyl; or R³ is a C₃₋₇ cycloalkyl, a 5-6 membered aryl,heteroaryl or heterocyclic ring, each optionally substituted with halo,cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, orfused with a carbocyclic or heterocyclic ring.
 5. The compound of claim4, wherein R³ is H, cyclopentyl, cyclohexyl, cycloheptyl,tetrahydropyran, morpholine, phenyl optionally fused to a 5-6 memberedheterocyclic ring, pyridinyl, imidazole, furan, pyrimidine, thienyl,C₁₋₆ straight or branched alkyl, or bicyclo[4.2.0]octa-1,3,5-triene. 6.The compound of claim 1, wherein said compound is selected from thegroup consisting of:

including the pharmaceutically acceptable salts thereof.
 7. Apharmaceutical composition comprising the compound of claim 1 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.